Alzheimer's Disease
Alzheimer's Disease
Last Section Update: 10/2024
Contributor(s): Debra Gordon, MS; Shayna Sandhaus, PhD; Chancellor Faloon, Health & Wellness Author
1 Overview
Summary and Quick Facts for Alzheimer's Disease
- Alzheimer’s disease is a neurodegenerative disorder characterized by cognitive decline that eventually leads to death. Estimates suggest that in the United States alone there will be 11 to 16 million individuals aged 65 and older diagnosed with Alzheimer’s disease by 2050.
- A comprehensive approach to Alzheimer’s disease treatment is required that acknowledges and targets the many possible factors underlying the changes in brain structure and function that drive this complex condition. In this protocol, you will learn about theories of Alzheimer’s disease, risk factors, conventional treatment, novel and emerging approaches, and the roles of hormone replacement, dietary and lifestyle management strategies, and targeted nutritional therapies.
- While available treatments may slightly improve symptoms, they do not alter the course of the disease. However, natural interventions such as Huperzine A and lipoic acid may help protect cognitive function and promote brain health.
What is Alzheimer’s Disease?
Alzheimer’s disease is a neurodegenerative disorder characterized by cognitive decline that eventually leads to death. The underlying cause of Alzheimer’s disease is not fully understood; however, it appears to be the consequence of many converging factors of aging, including accumulation of toxic protein aggregates in the brain, mitochondrial dysfunction, oxidative stress, and inflammation. Chronic infection with bacterial or viral pathogens also seems to play an underappreciated role in progression of the disease.
There is no cure for Alzheimer’s. And while available treatments may slightly improve symptoms, they do not alter the course of the disease. However, natural interventions such as huperzine A and lipoic acid may help protect cognitive function and promote brain health.
What are the Risk Factors for Alzheimer’s Disease?
- Advanced age
- Family history/carrying a genetic variant
- Certain infections
- Vascular conditions (eg, high blood pressure, diabetes)
- History of head trauma
- High homocysteine levels
- Nutrient deficiencies
- Silent strokes
- Central obesity (ie, high hip-to-waist ratio)
What are Medical Treatments for Alzheimer’s Disease?
- Cholinesterase inhibitors (eg, donepezil [Aricept], rivastigmine [Exelon], and galantamine [Razadyne])
- NMDA receptor blockers (eg, memantine [Namenda])
What are Emerging Therapies for Alzheimer’s Disease?
Note: Many of the therapies listed below are debated, with some studies that show benefit and others that do not. Alzheimer’s research to determine the efficacy of various treatments is always ongoing.
- Non-steroidal anti-inflammatory drugs (NSAIDs)
- Blood pressure lowering drugs
- Lithium
- Etanercept (Enbrel), a drug used for certain inflammatory conditions, may have benefits for Alzheimer’s disease.
- Granulocyte colony-stimulating factor (G-CSF), a growth factor that promotes creation of new neurons, has shown benefit in animal models.
- Brain-derived neurotrophic factor (BDNF), a signaling protein that declines with age and Alzheimer’s, is a potential therapy.
- Selective estrogen receptor modulators (SERMs)
- Vaccines to clear plaque from the brain
- Antibiotics
- Hormone replacement therapy, and others
What Dietary and Lifestyle Changes Can Be Beneficial for Alzheimer’s Disease?
- The Mediterranean diet has been linked to a reduced risk of Alzheimer’s and other neurodegenerative diseases.
- Low-calorie diets have been linked to a reduced risk of cognitive decline.
- Regular exercise can improve brain health.
What Natural Interventions May Be Beneficial for Alzheimer’s Disease?
- Huperzine A. Derived from the plant Huperzia serrata, huperzine A has a mechanism of action similar to existing Alzheimer’s drugs and has been shown to improve cognition in Alzheimer’s patients.
- Lion’s mane. Lion’s mane is a mushroom used traditionally in Asia to improve memory. Preclinical and small preliminary clinical trials show promise for improving cognition in Alzheimer’s.
- Lipoic acid. This antioxidant reduces inflammation and has been shown to slow disease progression in small clinical studies of Alzheimer’s patients.
- Acetyl-L-carnitine. Another antioxidant, acetyl-L-carnitine has been shown to benefit patients with mild cognitive impairment and mild Alzheimer’s.
- Panax ginseng. The Panax ginseng plant produces memory improvements. Alzheimer’s patients given a high dose saw improvements in their cognitive abilities.
- Vitamins C and E. Vitamins C and E are well known for their antioxidant properties. Supplementation has been shown to reduce the risk of developing Alzheimer’s.
- Omega-3 fatty acids. Supplementation with omega-3 fatty acids, such as docosahexaenoic acid (DHA), improved cognitive function and memory in people with age-related cognitive decline.
- Phosphatidylserine. Supplementation with phosphatidylserine, a natural component of cell membranes, improved cognition in elderly people with cognitive impairment.
- Coffee. Coffee consumption is linked with a reduced risk of Alzheimer’s and Parkinson’s disease. Long-term coffee intake may enhance working memory as well.
- B vitamins. B vitamins lower homocysteine levels, a risk factor for Alzheimer’s. Multiple studies have shown that low levels of B vitamins (B12, folate, niacin, etc.) are associated with an increased risk of Alzheimer’s and impaired cognitive function while higher levels are protective.
- Many additional natural interventions may be beneficial for cognitive health, including ginkgo biloba, curcumin, melatonin, vinpocetine, pyrroloquinoline quinone (PQQ), grape seed extract, and others.
2 Introduction
Alzheimer’s disease is a neurodegenerative disorder characterized by a decline in cognitive function that eventually leads to death (Upadhyaya 2010; Stern 2008; Knopman 2012; Mayo Clinic 2011). Research in Alzheimer’s disease has not yet identified a cure for the disease. Advanced age is a risk factor for development of the disease (Alzheimer’s Association 2012b; Knopman 2012).
With an increase in the aging population, the worldwide prevalence of Alzheimer’s disease has increased remarkably and is expected to continue to do so. Estimates suggest that in the United States alone there will be 11-16 million individuals aged 65 and older diagnosed with Alzheimer’s disease by 2050 (Zhao 2012; Tarawneh 2012).
Alzheimer’s disease appears to be the consequence of several convergent factors including oxidative stress, inflammation, mitochondrial dysfunction, and accumulation of toxic protein aggregates in and around neurons (Luan 2012; Teng 2012; Rosales-Corral 2012; Wang 2007; Fonte 2011; Ittner 2011). Emerging, intriguing research implicates chronic infection with several pathogenic organisms in the development and progression of Alzheimer’s disease as well (Miklossy 2011). Moreover, age-related changes such as declining hormone levels and vascular dysfunction are thought to contribute to some aspects of Alzheimer’s disease (Vest 2012; Barron 2012; Baloyannis 2012).
Conventional pharmacologic interventions target symptoms, but fall short of addressing underlying, contributing factors for Alzheimer’s disease. This results in a small reduction of symptoms, but does not halt or reverse disease progression (Sadowsky 2012; Alkadhi 2011).
A comprehensive approach to Alzheimer’s disease treatment is required that acknowledges and targets the many possible factors underlying the changes in brain structure and function that drive this complex condition (Sadowsky 2012).
3 Theories of Alzheimer's Disease
Research into the potential causes of Alzheimer’s disease has been frustrating. A number of processes are believed to contribute to the cognitive decline observed in Alzheimer’s disease. Brain deterioration in Alzheimer’s disease is thought to begin decades before symptoms become evident. Outlined below are several factors postulated to contribute to Alzheimer’s disease; each also represents a potential therapeutic target (Luan 2012; Teng 2012).
Senile Plaques
A prominent finding in Alzheimer’s disease is that senile plaques, which are comprised of “clumps” of the protein fragment amyloid beta, accumulate and cause cellular damage in key areas of the brain, especially the hippocampus, which is involved in memory consolidation and spatial navigation (Biasutti 2012). Aggregates of amyloid beta have been shown to contribute to oxidative damage, excitotoxicity, inflammation, cell death, and formation of neurofibrillary tangles (NFTs) (see below) (Massoud 2010). However, therapies aimed solely at reducing amyloid beta have proven disappointing, suggesting a more complex process is involved (Marchesi 2012; Schmitz 2004; Holmes 2008).
Neurofibrillary Tangles
Neurons contain a cellular skeleton made up of microtubules, secured in place by specialized proteins called tau. In Alzheimer’s disease, microtubules disintegrate and tau proteins “clump” together to form aggregates called neurofibrillary tangles or NFTs. NFTs function much the same as amyloid beta aggregates in that they initiate several process that lead to cellular dysfunction and death. Whether amyloid beta or NFTs arise first in Alzheimer’s disease is unclear, and this remains a heavily debated topic within the scientific community (Massoud 2010; Crespo-Biel 2012).
Acetylcholine deficit
A theory once widely advocated, but which has proved to be disappointing at addressing underlying disease progression, is the cholinergic hypothesis. This view suggests that Alzheimer’s disease is the consequence of insufficient synthesis of the neurotransmitter acetylcholine, which is fundamental in many aspects of cognition (Munoz-torrero 2008; Nieoullon 2010).
Clinical trials have shown medications that support acetylcholine signaling reduce symptoms, but do not reverse or halt the disease. Therefore, inadequate cholinergic neurotransmission is now viewed as a consequence of generalized brain deterioration observed in Alzheimer’s disease, rather than a direct cause. Nonetheless, drugs that modulate acetylcholine signaling are still a mainstay of symptomatic management of Alzheimer’s disease (Munoz-torrero 2008; Nieoullon 2010).
Oxidative Stress
Oxidative stress is a process in which highly reactive molecules called free radicals damage cellular structures. Free radicals are byproducts of normal metabolism, but during states of metabolic abnormality such as mitochondrial dysfunction (see below), they are created more rapidly and in greater quantity. In the case of Alzheimer’s disease, oxidative stress both facilitates some of the damage caused by amyloid beta and spurs its formation (Dong-gyu 2010; Hampel 2011).
Oxidative stress propagates Alzheimer’s disease via another route as well. As neurons become damaged, free iron accumulates on their surfaces and within nearby cells called microglia. Free iron causes radical formation and drives oxidative stress (Mandel 2006).
Inflammation
The inflammatory process appears to play an important role in the development of Alzheimer's disease. Glial cells, such as microglia, function to eliminate potential pathogens and harmful particles (eg, amyloid beta). However, this process, though helpful, can contribute to neuroinflammation (Twarowski 2023).
When high levels of amyloid beta accumulate in the brain, it activates the body’s immune response, resulting in inflammation that damages neurons (Salminen 2009). Part of the inflammatory response to amyloid beta appears to be facilitated by tumor necrosis factor-alpha (TNF-α) (Tobinick 2008a). TNF-α is a pro-inflammatory cytokine that is often found in high levels in serum and cerebral spinal fluid (CSF) of Alzheimer’s patients; it represents a potential target for novel Alzheimer’s disease therapies (Culpan 2011; Ardebili 2011; Tobinick 2008a).
Mitochondrial Dysfunction
Mitochondria are the energy power plants of cells; they generate energy in the form of adenosine triphosphate (ATP), which is necessary for cellular function. Mitochondrial dysfunction has been implicated in many age-related diseases, including Alzheimer’s disease (Chen 2011). One line of evidence that supports a link between Alzheimer’s disease and mitochondrial dysfunction is the finding that ApoE4, a genetic variant associated with Alzheimer’s disease and amyloid beta deposition within the brain, seems to play a role in disrupting mitochondrial respiratory chain function (Caselli 2012; Chen 2011; Polvikoski 1995).
Dysfunctional mitochondria are important mediators of amyloid beta toxicity (Leuner 2012). Mitochondrial dysfunction contributes to an increased burden of oxidative stress as well, which itself is another mediator of amyloid beta toxicity. Mitochondrial dysfunction and oxidative stress then drive the formation of additional amyloid beta, creating a vicious, self-propagating cycle that ultimately leads to neuron death (Leuner 2012).
Excitotoxicity
Glutamate is the most abundant excitatory neurotransmitter in the brain and is necessary for normal brain function. However, too much glutamatergic neurotransmission can be toxic to neurons, a phenomenon known as “excitotoxicity”. Excitotoxicity is thought to contribute to neuronal degeneration in Alzheimer’s disease because it is promoted by amyloid beta, neurofibrillary tangles, mitochondrial dysfunction, and oxidative stress among other factors (Danysz 2012).
Glutamate excitotoxicity is the result of over activation of N-methyl-D-aspartate (NMDA) receptors. Therefore, modulating this receptor is a way to lessen some of the damaging effects of excess glutamate signaling. The FDA has approved memantine (e.g., Namenda®), an NMDA receptor blocker, for the treatment of moderate to severe Alzheimer’s disease (Danysz 2012).
Loss of Sex Hormones
Evidence suggests that age-related loss of sex hormones – estrogen in women and testosterone in men – may contribute to Alzheimer’s disease. Although the specific mechanisms are unclear, sex hormones appear to protect the brain against the development of Alzheimer’s disease (Vest 2012; Barron 2012). For example, declining estrogen and testosterone levels seem to be associated with increased amyloid beta and tau abnormalities (Overk 2012).
Infections
An intriguing theory that remains largely unappreciated by the medical community is that chronic infection with a variety of pathogenic bacteria and/ or viruses may contribute to the development of Alzheimer’s disease. Research indicates that some common pathogens are consistently detected in the brains of Alzheimer’s patients. For example, a comprehensive analysis of studies found that Spirochetes, a family of bacteria, was detected in about 90% of Alzheimer’s patients and was virtually absent in healthy age-matched controls. Further statistical evaluation revealed a high probability of a causal relationship between Spirochetes infection and Alzheimer’s disease (Miklossy 2011).
Spirochetes and other bacteria can linger in the brain and drive inflammation and the formation of amyloid beta and neurofibrillary tangles, all of which are hallmarks of Alzheimer’s disease (Miklossy 2011). Moreover, laboratory studies indicate that amyloid beta is an antimicrobial peptide, suggesting its formation could be an adaptive response to infectious organisms (Soscia 2010). These and other findings have led some researchers to hypothesize that “…early intervention against infection may delay or even prevent the future development of [Alzheimer’s disease]” (Honjo 2009).
There is some evidence suggesting periodontal disease (gum disease) is associated with an increased risk of developing Alzheimer's disease (Beydoun 2020). In a study of elderly participants, those with evidence of amyloid beta in their brains had significantly higher scores of periodontal dysbiosis (Kamer 2021). Participants with periodontal dysbiosis had overgrowth of harmful bacteria, such as those from genera Treponema, Porphyromonas, and Tannerella, along with decreased levels of healthy bacterial genera such as Rothia and Corynebacterium.
A recent article published in Science Advances provides intriguing evidence that Alzheimer’s disease could be caused, in part, by infection with Porphyromonas gingivalis,a keystone pathogen of chronic periodontitis and significant risk factor for developing amyloid beta plaques, dementia, and Alzheimer’s disease. P. gingivalis produces virulence factors called gingipains—proteases essential for its survival and pathogenicity. The authors hypothesized that gingipains promote neuronal damage in Alzheimer’s patients and may contribute to the pathogenesis of Alzheimer’s disease.
The scientists began by studying and comparing brain tissue samples from Alzheimer’s disease patients and neurologically normal controls. They found that the gingipain load was significantly higher in Alzheimer’s disease samples than in controls, indicating gingipain load is correlated with Alzheimer’s disease diagnosis and disease markers. Interestingly, the scientists found a portion of the “healthy” brains were infected as well indicating that “… brain infection with P. gingivalis is not a result of poor dental care following the onset of dementia or a consequence of late-stage disease, but an early event that can explain the pathology found in middle-aged individuals before cognitive decline.”
In addition to identifying P. gingivalis in the brains and cerebrospinal fluid of Alzheimer’s disease patients, they also developed potent small molecule gingipain inhibitors which protected neurons from P. gingivalis-induced cell death. Mouse studies also showed the inhibitors could protect against neurodegeneration caused by P. gingivalis infection and provided direct evidence that oral infection with P. gingivalis can result in brain infiltration, increases in the conventional Alzheimer’s disease biomarker Aβ1-42, and neurodegeneration. COR388, an analog of the most potent inhibitor with better oral bioavailability and central nervous system penetration, was shown to treat an existing brain P. gingivalis infection and reduce bacterial load, Aβ1-42 levels, and tumor necrosis factor-α levels (Dominy 2019).
These findings offer compelling evidence that P. gingivalis infection and gingipains in the brain play an important role in the pathogenesis of Alzheimer’s disease. Furthermore, it demonstrates that oral administration of a small molecule gingipain inhibitor is effective for blocking gingipain-induced neurodegeneration and reducing bacterial load in mouse brains.
Exposure to Aluminum
Aluminum’s role in the pathogenesis of Alzheimer’s disease has been debated for well over a century. Aluminum is neurotoxic even in small amounts, and some scientists suggested accumulation in the brain over a lifetime may contribute to the development of Alzheimer’s disease (Tomljenovic 2011; Colomina 2017). Aluminum has been linked to accumulation of amyloid beta and tau proteins (Huat 2019). In a study of brain tissue from patients with familial Alzheimer’s disease, aluminum was found near modified tau proteins characteristic of neurodegenerative disease in the temporal cortex. Aluminum has also frequently been found near amyloid beta plaques in the brain’s coretex (Mold 2021). The nature of the potential connection between aluminum and Alzheimer’s disease requires further study.
Herpesviruses and Alzheimer’s/Dementia Risk
Herpes-type viruses, such as herpes simplex virus type 1, Epstein-Barr virus (most common cause of mononucleosis), and the varicella zoster virus (the cause of chickenpox and shingles), may increase the risk of Alzheimer’s and dementia (Nath 2019). Preclinical research has shown that herpesviruses could potentially contribute to Alzheimer’s by seeding amyloid-beta plaques, which are believed to be partly responsible for the symptoms of Alzheimer’s (Eimer 2018).
In a cell culture study, human-induced neural stem cell cultures were infected with the varicella virus and/or herpes simplex virus type 1. The cells infected with only the varicella virus showed detrimental glial cell changes and increased pro-inflammatory cytokines, but there was no accumulation of amyloid-beta or tau proteins. Interestingly, cells that were latently (inactively) infected with herpes simplex-1 had reactivation of the herpes simplex-1 virus upon varicella virus infection, which led to an accumulation of tau and amyloid-beta. More research is needed to understand the potential connection between these two different herpesviruses and their association with Alzheimer’s (Cairns 2022).
Some evidence supports the theory that the varicella virus might reside latently in the brain, and that upon reactivation it can cause problems that could contribute to Alzheimer’s (Lophatananon 2021). A meta-analysis of epidemiological studies published in 2019 found that past infection does not increase the risk. One cohort study found that reactivation of the virus, as shingles of the eye (Herpes zoster ophthalmicus), was associated with an increased risk (Warren-Gash 2019).
A relatively small observational study in people suffering from disorientation or memory loss, published in 2021, found that vaccination against shingles reduced the risk of dementia (Lehrer 2021). In 2022 observational findings from a cohort including over 300,000 adults over age 65 years and without dementia showed that herpes zoster vaccination, compared with no vaccination, was associated with a 31–35% lower risk of dementia and a lower risk of Alzheimer’s disease (Scherrer 2022).
In 2023 news came out of a large population-based study that deemed the relationship between shingles and Alzheimer’s to be causal (Eyting 2023). The study included a total of 282,541 elderly people in Wales that either received the shingles vaccine on or after September 1st, 2013 or were ineligible to receive the vaccine as part of a policy change. Participants were followed until 2020 and the results showed that those who were vaccinated had a nearly 20% relative risk reduction in Alzheimer’s disease compared with controls (ie, people who were ineligible for vaccination). This translates to a 3.5% absolute risk reduction. The researchers attempted to ensure no confounding factors were at play for the differences between groups. Although the researchers who conducted this study interpreted their findings as providing causal evidence that shingles vaccination reduced the risk of Alzheimer’s disease, their report had not undergone peer review as of the time of this writing. More research should be conducted to confirm these results.
In 2024, a study was published that showed further evidence that the shingles vaccine is associated with lower risk of dementia. The study used a natural experiment opportunity created in the United States when in October 2017, live attenuated shingles vaccines were rapidly abandoned in favor of the more protective recombinant vaccines. Within six years of vaccination, those who received the recombinant vaccine, compared with those who received the attenuated-vaccine, had a 17% increase in time without a diagnosis of dementia, equal to 164 days more than with the attenuated live vaccine (Taquet 2024). Shortly after the publication of this study, results from a prospective study on shingles history and cognitive decline were published. Drawn from data from three large cohorts totaling close to 150,000 people, this study found that people with a history of shingles had a greater risk of significant cognitive decline, ranging from 14–24% greater, than those with no history of shingles (Yeh 2024).
Influenza and pneumonia may activate dormant herpesviruses, and research has shown that vaccination against influenza and pneumonia is associated with a reduced risk of Alzheimer’s (Lehrer 2022). In a cohort study that included over 900,000 individuals, the incidence of Alzheimer’s in people over age 65 years was 5.1% for people vaccinated against the flu compared with 8.5% in the unvaccinated people over a median follow-up of 46 months (Bukhbinder 2022). In a different cohort study of people between ages 65 and 75 years, those who were vaccinated against pneumonia had 30% lower odds of Alzheimer’s compared with unvaccinated controls (Ukraintseva 2020).
4 Risk Factors for Alzheimer's Disease
Several factors influence the risk of Alzheimer’s disease. Some are modifiable, such as obesity and nutrient deficiencies, but others, such as carrying the ApoE4 gene, are not. Below is a partial list of factors known to be associated with an increased risk of Alzheimer’s disease (Yilmaz 2012; Daviglus 2011; Harrison 2012; Hinterberger 2012; Luchsinger 2012; van Himbergen 2012; Stern 2008; Blum 2012; Miklossy 2011; Fenton 2023; Xiong 2022).
- Advancing age
- Family history of Alzheimer’s disease
- Carrying the ApoE4 genetic variant
- Certain bacterial infections
- Vascular risk factors (e.g., diabetes, atherosclerosis, high blood pressure, high cholesterol) appear to encourage the development of phenomena associated with Alzheimer’s disease such as accumulation of amyloid beta (Kalaria 2012).
- History of head trauma
- High homocysteine levels
- Nutrient deficiencies
- Silent strokes
- Central obesity (i.e., high waist-to-hip ratio)
- Inadequate sleep
5 Diagnosis
Although autopsy provides a definitive diagnosis, there is no single test to definitively diagnose Alzheimer’s disease in the living (Alzheimer’s Association 2012a; Uzun 2011). Alzheimer’s disease is diagnosed by exclusion in the living. In other words, physicians must confirm that neurological deficits are not being caused by other conditions (e.g., vascular dementia). The standard diagnostic strategy comprises collection of detailed patient history data, standardized assessment of cognition and functional status (e.g., Mini-Mental State Examination [MMSE]), laboratory testing, and brain imaging examinations such as magnetic resonance imaging (MRI), positron emission tomography imaging (PET), and single-photon emission computed tomography (SPECT) (Biasutti 2012).
Discovering more specific biomarkers for Alzheimer’s disease may lead to the development of more accurate diagnostic tools for early diagnosis (Biasutti 2012). Some genetic biomarkers that raise the risk of Alzheimer’s disease have already been identified (Kasper 2004; Engelborghs 2012).
6 Medical Treatment
Three classes of medication are available for treatment of Alzheimer’s disease (Press 2024; Press 2021):
- monoclonal antibodies;
- cholinesterase inhibitors (e.g., donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon); and
- the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Namenda)
In clinical trials, all have demonstrated modest benefits of variable or uncertain clinical significance. Therefore, it is important that people with Alzheimer’s disease and their caregivers discuss the benefits and risks of these medicines with their doctor to determine whether they are appropriate in each unique case. Treatment with these medicines can be initiated on a trial basis with attentive monitoring of benefits and adverse effects to assess whether longer-term continuation is warranted (Press 2024; Press 2021).
Monoclonal Antibodies (mABs)
Monoclonal antibodies (mABs) are used in the treatment of several diseases. In recent years, three mABs have garnered substantial attention following approvals for use in Alzheimer’s disease. These are (AAN 2024):
- Aducanumab (Adulhelm), approved in 2021 (permanently off market since 2024)
- Lecanemab (Leqembi), approved in 2023
- Donanemab (Kisunla), approved in 2024
These drugs are all designed to target amyloid beta in the brain. The mABs are believed to work by activating microglia, a type of immune cell in the brain. Activated microglia are thought to facilitate amyloid beta elimination through a process called phagocytosis (Cummings 2024). This is a process by which a cell engulfs and digests particles, microorganisms, or foreign substances.
Prior to the approval of aducanumab, there had not been a new drug approval for Alzheimer’s disease since 2003 (Servick 2021). Aducanumab was granted approval through the FDA’s accelerated approval program, and is considered one of its most controversial drug approvals in recent history (Press 2021; Servick 2021; Belluck 2021). Aducanumab was taken off the market in January 2024 due to refusal of insurance coverage and lack of enthusiasm by physicians to prescribe it (Dyer 2024).
Lecanemab and donanemab, the two remaining available monoclonal antibodies drugs, differ in how they target amyloid beta. Lecanemab has a strong affinity for protofibrils of soluble amyloid beta, which are highly toxic to neurons, as compared to amyloid beta monomers or insoluble fibrils (van Dyck 2023). In contrast, donanemab targets a form of amyloid beta found only in established brain plaques (Gu 2024; Sims 2023). Both drugs are approved to treat early symptomatic Alzheimer’s disease in patients with mild cognitive impairment or mild dementia and confirmed amyloid-beta pathology. They are administered viaIV infusion, every two weeks for lecanemab and every four weeks for donanemab (NLM 2024; NLM 2023).
Lecanemab was approved following the results of an 18 month, randomized, controlled, phase 3 trial (MacMillan 2023). The trial recruited a total of 1,795 people, aged 50–90 years, with early Alzheimer’s disease randomized to receive lecanemab or placebo. The primary endpoint was defined as changes in Clinical Dementia Rating Sum of Boxes (CDR-SB) score at 18 months. Over the course of the study, both groups experienced a decline in cognition using this scoring system, but the decline was more severe in the placebo group. One of the secondary endpoints in this trial was changes in amyloid beta on PET scans, which was evaluated in a subgroup of 698 people. Compared with baseline, those who received lecanemab had significant reductions in brain amyloid burden, whereas the placebo group’s amyloid burden slightly increased (van Dyck 2023).
Donanemab was approved following the results of a randomized controlled trial similar in design to the trial on lecanemab (Harris 2024). A total of 1,736 people, age 60–85, with early symptomatic Alzheimer’s disease were randomized to receive donanemab (n = 860) or placebo (n = 876); 1,320 completed the 76-week trial. The primary outcome was twofold: change in cognitive decline, measured by the integrated Alzheimer Disease Rating Scale (iADRS) in the overall study population, and the same measurement in a subset of participants with low-to-medium levels of tau protein pathology as determined by PET scan at baseline. At the end of the trial, those in the donanemab group who had a low-to-moderate amyloid beta burden had a 35.1% slower cognitive decline, compared with placebo, based on the iADRS scale. In the overall study population that included all levels of tau pathology, there was a 22.3% slowing of disease progression in the donanemab group—again based on iADRS—compared with those who received placebo. This demonstrated that the treatment was more efficacious when administered earlier in the disease progression. One of many secondary outcomes measured was change in amyloid beta as measured by PET scan. Compared with baseline, those who received donanemab had significantly reduced amyloid burden, whereas the placebo group remained about the same. Thirteen percent of those randomized to donanemab dropped out of the trial due to adverse events (Sims 2023).
Adverse Effects of Monoclonal Antibodies
Anti-amyloid agents are associated with a significant risk of adverse effects (Press 2021). In the clinical trials leading to drug approval, the most common side effects of these two drugs were infusion-related reactions (NLM 2024; NLM 2023). The most common potentially serious side effects of the drugs are amyloid related imaging abnormalities (ARIA). Although usually asymptomatic and detected only on brain imaging, this syndrome can lead to signs and symptoms such as headache, confusion, dizziness, and seizures, and has been associated with excessive neuroinflammation. It can present as ARIA-E, which refers to edema (swelling and fluid leakage), and ARIA-H, which usually refers to small amounts of brain bleeding (microhemorrhages) or leakage of small amounts of iron-containing blood products. Less commonly, large bleeds (macrohemorrhages) or hemorrhagic stroke can occur. Both types can also occur together (Withington 2022). In both large pre-approval trials of the two anti-amyloid therapies, incidence of either type of ARIA was two or more times as frequent in the treatment group compared with placebo (van Dyck 2023; Sims 2023).
Importantly, the greatest genetic risk factor for Alzheimer’s, having two copies of APOE-e4, also increases the risk of developing ARIA after receiving these antibody-based therapies.
In the lecanemab trial, the rates of ARIA-H and ARIA-E, respectively, were about (Foley 2024):
- 39% and 33% among those with two copies of APOE-e4
- 14% and 11% among those with one copy of APOE-e4, and
- 12% and 5% among those without APOE-e4.
In the donanemab trial, ARIA-H was not reported. ARIA-E occurred in:
- 41% of those with two copies of APOE-e4,
- 23% of those with one copy of APOE-e4, and
- 16% of those without APOE-e4.
Importantly, these mAB therapeutics only modestly slow the progression of Alzheimer’s disease, and do not restore or improve cognitive function (Press 2021). Although there were statistically significant differences in those receiving treatment compared with placebo, many experts in this field question whether these drugs produce clinically meaningful benefits, and many physicians recommend against prescribing them (Press 2021; Ebell 2024). The decision to treat Alzheimer’s disease with a mAB drug should be carefully weighed against the high treatment cost and potential adverse effects.
Cholinesterase Inhibitors
Three cholinesterase inhibitors are approved for the treatment of mild-to-moderate dementia attributable to Alzheimer’s disease: donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne). They are symptomatic therapy; not thought to be neuroprotective or alter disease progression; and doubt persists about their benefit for long-term outcomes. Nevertheless, their use has been found to be associated with a roughly 23–40% reduction in overall mortality across numerous studies, over a follow-up period of 8–13 years. This effect appears to be more robust for donepezil and galantamine than rivastigmine. They are also known to delay the progression of cognitive decline, though this effect is small on average and of uncertain clinical importance (Press 2024; Press 2021; Truong 2022; Nielsen 2022; Zuin 2022). Response to cholinesterase inhibitors in Alzheimer’s disease is highly variable, so while some patients receive no benefit, others may see significant clinical improvement. It is for this reason that individualized evaluation and management of this therapy is critical (Press 2024; NICE 2018).
Memantine
Memantine, an NMDA receptor antagonist (blocker), exhibits neuroprotective properties, and has a modest benefit in individuals with moderate-to-severe Alzheimer’s disease. When added to cholinesterase therapy, it has resulted in small improvements in cognition and overall outcomes. Memantine has no benefit in cases of mild Alzheimer’s disease. It is characterized by a favorable adverse effect profile (Press 2021; McShane 2019).
7 Novel and Emerging Approaches
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Evidence from population-based studies suggests beneficial effects of treatment with non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease, although these effects have not been reproduced in clinical trials (Sastre 2010). NSAIDs affect the pathology of Alzheimer’s disease by inhibiting cyclooxygenase (COX) enzymes, which contribute to inflammation.
NSAIDs appear to prevent cognitive decline in older adults if started in midlife (prior to age 65) rather than late in life (Hayden 2007; Sastre 2010). Unfortunately, NSAIDs, even at normal dosages, have been associated with significant adverse effects. Long-term use of NSAIDs is associated with gastrointestinal, kidney, and cardiovascular complications (Sastres 2010; William 2011; Ejaz 2004). Low-dose aspirin, however, might be effective in reducing Alzheimer’s incidence and side effects are relatively rare when only 81 mg a day are taken.
Blood Pressure Lowering Drugs
It has been hypothesized that treating cardiovascular risk factors might be an effective means of preventing or treating dementia syndromes, including Alzheimer’s (Qiu 2012). Specifically, elevated blood pressure during midlife appears to be associated with Alzheimer’s development in late life. This effect may be caused by a link between high blood pressure and poor amyloid beta clearance from the brain (Shah 2012).
Drugs normally used to treat hypertension, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and calcium channel blockers, have been considered as potential Alzheimer’s therapies (Qiu 2010). Some research suggests that these drugs mildly reduce cognitive decline, and may reduce risk of Alzheimer’s development and progression (Forette 1998; Hajjar 2008; Trenkwalder 2006). In addition to the suggested reduction in amyloid beta clearance, high blood pressure may lead to cerebrovascular changes, including reduced cerebral blood flow. Reduced cerebral blood flow may accelerate Alzheimer’s disease progression. In a randomized, double-blind, placebo-controlled study, 58 participants with mild-to-moderate Alzheimer’s took nilvadipine (a calcium channel blocker) or placebo for six months. In addition to reduced blood pressure, participants in the treatment group had increased cerebral blow flow in the hippocampus, an area of the brain important for forming memories and other essential tasks. These results suggest a beneficial cerebrovascular effect of using antihypertensive agents in Alzheimer’s disease (de Jong 2019).
Etanercept (Enbrel®)
Etanercept (Enbrel®), a biological inhibitor of the cytokine TNF-α, is approved for the treatment of certain inflammatory conditions (e.g., rheumatoid arthritis, plaque psoriasis). When formulated as a perispinal injection and administered to Alzheimer’s patients, preliminary research reports suggest that Enbrel® leads to sustained improvement in cognitive function that was evident within minutes (Tobinick 2008a,b; Tobinick 2012).
Granulocyte Colony-Stimulating Factor (G-CSF)
Granulocyte colony-stimulating factor (G-CSF) is a growth factor that stimulates production of certain white blood cells. It also supports the creation of new neurons in the brain and modulates cholinergic neurotransmission (Jiang 2010). Lower levels of G-CSF have been identified in Alzheimer’s patients compared to healthy individuals (Laske 2009). An animal model of Alzheimer’s found that injections of G-CSF not only rescued compromised memory and cognitive functions, but also raised levels of acetylcholine (Tsai 2007). A study at the University of South Florida seeks to evaluate the cognitive effects of administering G-CSF to Alzheimer’s patients (Clinicaltrials.gov).
Brain-Derived Neurotrophic Factor (BDNF)
BDNF (Brain-Derived Neurotrophic Factor), a signaling protein active in the brain, facilitates the growth of new neurons and synapses and also reverses neuronal atrophy. Since BDNF levels decline with age and Alzheimer’s disease, administration of BDNF has been suggested as a potential therapy for memory loss (Li 2009). Injecting BDNF into the brains of rodents and primates reversed synaptic damage, cell death, cognitive decline, and memory deficits (Nagahara 2009). Intensive research in rodents has led to the first promising clinical trials of intracerebral neurotrophin for AD (Schulte-Herbrüggen 2008).
Lithium
Lithium is a mineral used as a mood stabilizer, particularly in the treatment of bipolar disorder and major depression (Forlenza 2014). Animal and laboratory research indicate lithium may have neuroprotective effects and may preserve cognitive function in models of cognitive decline and Alzheimer’s disease (Tan 2010; Choi 2010; Cabrera 2014; De-Paula, Gattaz, 2016). In humans, lithium appears to increase brain mitochondrial functioning, reduce brain oxidative stress and markers of inflammation, promote production of BDNF, and benefit regions of the brain involved in memory and cognitive activities (Forlenza 2014; De-Paula, Kerr, 2016).
Lithium supplementation may enhance cognitive function (Tsaltas 2009; Rybakowski 2016). In a pilot study, patients with Alzheimer’s disease treated with 300 micrograms lithium per day (at least 3000 times lower than typical doses used to treat bipolar disorder) for 15 months experienced no change in cognitive performance versus their untreated counterparts who experienced significant cognitive losses (Nunes 2013). In a pilot trial in 45 subjects with amnestic mild cognitive impairment (a condition that frequently progresses to Alzheimer’s disease), those who received lithium were less likely to develop Alzheimer’s disease over a 12-month period compared with placebo, although this difference was small and not statistically significant (Forlenza 2011). Findings from a study using a mouse model of Alzheimer’s disease suggest pyrroloqinoline quinone may enhance the benefits of lithium (Zhao 2014).
The neuroprotective effect of lithium appears to be related to its ability to inhibit an enzyme called glycogen synthase kinase 3. By inhibiting glycogen synthase kinase 3, which catalyzes reactions that join phosphates to tau proteins, lithium helps regulate tau protein phosphorylation and prevent neurofibrillary tangle formation (Houck 2016; Alvarez 2002; Engel 2008). Glycogen synthase kinase 3 inhibition has also been associated with reduced amyloid production (Zhang 2011; Rockenstein 2007). Furthermore, animal and laboratory research show lithium treatment may increase brain levels of a neuroprotective protein called beta-cell lymphoma 2 (Bcl-2) (Manji 2000).
Because doses of lithium used to treat bipolar disorder (typically 900–1800 mg per day) can cause a number of side effects (Gitlin 2016), including kidney toxicity (Azab 2015) and brain cerebellar toxicity and atrophy (shrinking) (Adityanjee 2005), researchers have been monitoring the effects of long-term use of lower doses. A preliminary, randomized, controlled trial in 61 older subjects with mild cognitive decline receiving low-dose lithium found no significant evidence of kidney damage after four years of treatment; however, lithium-treated subjects had higher incidence of weight gain, decreased thyroid function, new-onset diabetes, and abnormal heart rhythms. The lithium doses used in this study were ≥ 150 mg per day, and individualized to maintain serum levels between 0.25 and 0.50 mmol/L (Aprahamian 2014). While lithium appears to hold potential for people with Alzheimer’s disease, these findings point to more research needed to determine ideal dosing and long-term safety.
Selective Estrogen Receptor Modulators (SERMs)
Selective estrogen receptor modulators are drugs that either increase or decrease estrogen signaling, depending on the tissue type (McDonnell 2002). Currently, the most studied and clinically relevant SERMs are tamoxifen and raloxifene. Tamoxifen is best recognized as a potent antagonist (blocker) of estrogen action in breast tissue. However, low concentrations of tamoxifen have been noted to protect cultured neurons from amyloid beta and glutamate toxicity (O’Neill 2004). In postmenopausal women, raloxifene, at a dose of 120 mg/day, has been linked with reduced risk of cognitive impairment and development of Alzheimer’s disease (Yaffe 2005).
Vaccines
Vaccines are being developed in hopes of clearing amyloid beta from the brains of Alzheimer’s patients immunologically (Upadhyaya 2010). Initial research suggests a mechanistic possibility that this approach could work (Holmes 2008), but many obstacles still impede the development of clinically effective vaccines for Alzheimer’s disease (St. George-Hyslop 2008). For example, some studies suggest that simply eliminating amyloid beta may not be sufficient, and that targeting other aspects of Alzheimer’s pathology in conjunction with amyloid beta vaccination may have a better chance of success (Aranda-Abreu 2011).
Anti-apoE4 Immunotherapy
The variant apolipoprotein E4 (ApoE4) gene is one of the strongest genetic risk factors for late-onset Alzheimer’s disease (Kim 2012; Theendakara 2018). In mice, immunotherapy targeting human ApoE has been shown to reduce amyloid beta levels in the brain (Kim 2012). Amyloid beta can form deposits in the cerebral vasculature as well (cerebral amyloid angiopathy). In a mouse model with amyloid plaque in the brain as well as cerebral amyloid angiopathy, treatment with an anti-human ApoE antibody reduced both brain amyloid plaque and cerebral amyloid angiopathy. When the researchers used an antibody specific to amyloid beta, rather than ApoE, it reduced brain amyloid plaque but had no effect on cerebral amyloid angiopathy. In addition, the anti-amyloid beta antibody worsened brain microhemorrhages while the anti-human ApoE antibody did not. The anti-human ApoE antibody improved the function of cerebrovascular arteries and reduced pro-inflammatory genes in the cortex as well. These findings suggest that targeting ApoE with immunotherapy may reduce amyloid beta deposits while protecting the brain vasculature (Xiong 2021), but clinical trials are needed to confirm these results.
Antibiotics
As mentioned above, the theory that Alzheimer’s disease could be caused by infectious organisms is gaining traction within the scientific community. Based upon these findings, it has been proposed that antibiotics may represent a viable treatment for Alzheimer’s disease (Miklossy 2011).
Early clinical trials have noted marked improvements in Alzheimer’s patients following antibiotic treatment. In one such trial, 100 subjects with probable Alzheimer’s disease were treated with the antibiotics doxycycline and rifampin for three months and followed for a year. At six months post-treatment, subjects who received antibiotics displayed significantly less cognitive decline than those who received a placebo, and the effect was even more pronounced at 12 months. Antibiotic recipients also showed less behavioral dysfunction at three months. The researchers concluded that “therapy with doxycycline and rifampin may have a therapeutic role in patients with mild to moderate [Alzheimer’s disease]” (Loeb 2004). Another smaller trial found Alzheimer’s patients treated with 100 mg daily of the antibiotic D-cycloserine displayed significantly improved scores on a standardized assessment of cognitive function (Tsai 1999).
However, subsequent trials have failed to replicate these results. The Doxycycline and Rifampin for Treatment of Alzheimer’s Disease (DARAD) trial enrolled 406 patients with mild-to-moderate Alzheimer’s disease and treated them with doxycycline and rifampin for a year. There were no beneficial effects seen with the treatment (Molloy 2013). Additionally, a review of four studies found that D-cycloserine did not have a positive effect on cognitive outcomes in Alzheimer’s disease patients (Laake 2002). It is possible that the success of antibiotics in Alzheimer’s disease treatment hinges on the presence of an actual infection, such as with Spirochetes (a family of bacteria) and Porphyromonas gingivalis. The lack of such an infection may make antibiotic treatment unnecessary and ineffective.
It has become clear that the gut microbiome plays a significant role in brain health. In fact, Alzheimer’s disease may be associated with alterations in the microbiome, such as dysbiosis, which may be a source of infection and neuroinflammation. As such, modifying the microbiome with antibiotics or probiotics in Alzheimer’s disease is an interesting ongoing area of research (Angelucci 2019). However, the root cause of Alzheimer’s disease is still unclear, and it may be the case that different approaches should be taken depending on the individual patient. The future of antibiotics in Alzheimer’s disease treatment will depend upon the results of further preclinical and clinical studies.
Piracetam
Piracetam has been studied in a wide-range of patient populations and has demonstrated small benefits in a variety of models of neurological disorders. Multiple mechanisms for the observable effects of piracetam on brain function have been proposed, though a precise description of its mode of action has yet to be elucidated. Preliminary studies suggest that piracetam may modulate the signaling of multiple neurotransmitter receptors, and improve neuronal membrane fluidity (Malyka 2010; Muller 1997).
A comprehensive review that assessed the efficacy of piracetam in older subjects suggests that the drug may provide appreciable benefits for cognitive dysfunction. The reviewers concluded that “…the results of this analysis provide compelling evidence for the global efficacy of piracetam in a diverse group of older subjects with cognitive impairment” (Waegemans 2002). Additionally, a piracetam analog called levetiracetam was shown to reverse synaptic and cognitive deficits in an animal Alzheimer’s model (Sanchez 2012).
Zileuton
5-lipoxygenase (5-LO) is an enzyme that produces several pro-inflammatory lipid molecules, most of which are known as leukotrienes (Poeckel 2010; Hedi 2004). 5-LO and some of the leukotrienes it produces have been implicated in the inflammation that accompanies various chronic diseases, including Alzheimer’s disease (Vagnozzi 2017; Joshi 2014; Chinnici 2007). These inflammatory mediators have also been implicated in other tauopathies, which are neurodegenerative conditions in which toxic protein deposits, known as tau protein, accumulate inside neurons. Alzheimer’s disease is a type of tauopathy (Giannopoulos 2018a; Chu 2016).
A 2018 study suggests zileuton (Zyflo), a leukotriene inhibitor approved over two decades ago to treat asthma, may have the potential to reduce neurodegeneration associated with tau protein accumulation (Israel 1996; Watkins 2007). Using an animal model of neurodegeneration, the study tested whether inhibiting leukotriene synthesis could help after cellular damage in the nervous system has already started. Twelve-month-old mice with a tauopathy were randomized to receive zileuton or placebo for 16 weeks (Giannopoulos 2018b). As expected, at the beginning of the study memory and spatial learning were impaired in the mice with the tauopathy compared with control mice (Giannopoulos 2018b). Zileuton reduced these behavioral impairments. When the brains of the animals were examined, mice that received zileuton had about 90% fewer leukotrienes in their brains and about 50% less tau protein. The animals treated with zileuton also had decreased neuroinflammation and increased levels of three biochemical markers that reflect synaptic integrity (Giannopoulos 2018b).
Other studies also report benefits with zileuton treatment in neurodegenerative diseases. In a mouse model of Alzheimer’s disease, three months of zileuton treatment significantly decreased amyloid-beta levels between the neurons and improved cognitive function (Di Meco 2014). Another study on the same mouse model of Alzheimer’s disease showed that zileuton treatment led to a significant improvement in working memory and communication among brain cells (Giannopoulos 2014). Similar findings have been reported in other preclinical studies as well (Chu 2013; Chu 2011). Moreover, in rodent models of stroke, zileuton decreased inflammation, protected against brain damage, and improved neurological deficits (Tu 2016; Silva 2015). Zileuton also inhibited 5-LO activation and cell injury in a laboratory model of Parkinson’s disease (Zhang, Zhang 2011). In a laboratory study, zileuton protected mouse neurons against chemical toxicity caused by exposure to glutamate (Liu 2015).
Klotho
Klotho, named after one of the goddesses of destiny in Greek mythology, is a gene encoding the Klotho protein, which plays a crucial role in promoting longevity (Prud'homme 2022). Lower blood plasma levels, which is also known to correlate with CSF levels (Kundu 2022), of the Klotho protein have been linked to various age-related diseases, including chronic kidney disease, cardiovascular diseases, osteoporosis, and cognitive decline. As a result, increasing Klotho levels through gene therapy or recombinant protein administration is being explored as a potential treatment for age-related conditions like Alzheimer’s (Abraham 2022).
It was first shown in the late 1990’s that mutations in the Klotho gene led to systemic aging and reduced lifespan in mice (Kuro-o 1997). This discovery was confirmed by numerous subsequent mice studies (Kurosu 2005; Motoko 2008). Klotho appears to modulate the aging process by regulating several key pathways linked to aging, such as insulin signaling and Wnt signaling (Kanbay 2024). In a series of experiments conducted at University of California-San Francisco, it was demonstrated that elevating Klotho levels in Alzheimer’s mouse models mitigated premature mortality, cognitive impairment, and behavioral issues. Klotho appeared to increase the concentration of specific receptors at neuronal synapses, potentially boosting neural communication (Dubal 2015). In addition, it was found that overexpressing Klotho in the brain alleviated Alzheimer's-like pathology and improved cognitive deficits in mouse models (Zeng 2019). Recombinant Klotho administration also improved cognition in aged rhesus monkeys (Castner 2023).
In humans, Klotho blood serum levels are correlated with cognitive health. Researchers often employ the MMSE to screen for dementia, with higher scores indicating better cognitive function. Studies revealed that participants who scored higher on the Mini-Mental State Examination exhibited higher levels of Klotho (Kundu 2022; Linghui 2023). It was shown that older adults with Alzheimer's have lower levels of Klotho protein in their CSF compared to those without Alzheimer’s, concentrations averaging 664 pg/mL versus 776 pg/mL, respectively (Semba 2014). It has also been shown that individuals with the lowest blood levels of Klotho have a significantly increased risk of severe deep white matter lesions, which are commonly associated with various neurological conditions, including vascular dementia, Alzheimer's disease, and multiple sclerosis (Kuriyama 2018).
Interventions aimed at enhancing the level of Klotho are being explored as a possible strategy to treat or prevent the onset of Alzheimer’s in individuals at high risk. Several methods have been proposed, including administration of small molecule drugs, protein replacement therapy, senolytic therapy, exercise regimens, and recombinant gene therapy; however, these approaches have yet to be validated by interventional clinical studies in patients with Alzheimer’s disease (Kundu 2022; Zhu 2022; Corrêa 2022).
TB006
As of mid-2024, TB006—a monoclonal antibody and investigational new drug under development by the company TrueBinding—is approved for compassionate use. TB006 targets galactose-specific lectin 3 (galectin-3), a protein involved in the formation of neurotoxic amyloid beta oligomers and plaques, and with neuroinflammation (TrueBinding 2024a; TrueBinding 2024b). Galectin-3 is associated with activation of microglia and cognitive impairment, and may play a role in several different neurodegenerative diseases, though it may be neuroprotective under certain conditions (Garcia-Revilla 2022). In addition, galectin-3 has been demonstrated to be elevated in the hippocampus, cortex, and CSF of people with Alzheimer’s disease; and the presence of microglia that express galectin-3 is associated with amyloid beta plaque and tau tangles in Alzheimer’s (Boza-Serrano 2022). This has led to special interest in galectin-3 as a possible treatment target.
Microglia are immune cells that play a crucial non-immune role in brain development. Later in life, in brain injuries and in diseases affecting the central nervous system, they can be harmful or helpful depending on the situation (Li 2018). This can include scavenging of amyloid beta and tau, which can be beneficial. At later stages of Alzheimer’s, overactivation of microglia from chronic inflammation and excessive oxidative stress may lead to neurotoxicity (Merighi 2022).
In an early-stage (phase-1b/2) trial, safety and short-term, preliminary efficacy was assessed in a total of 157 people, aged 50 and over, with mild-to-severe Alzheimer’s disease. The participants were randomized to receive a total of five intravenous infusions of TB006 weekly, as part of one of three ascending dosage groups, or a placebo for one month (Bryson 2023; TrueBinding Inc 2023). They were followed for up to 104 days. Compared to baseline, by day 36 the treatment group had significant improvements in the Mini-Mental State Examination, one of the trial’s secondary outcomes. At that same time point, blood levels of a toxic form of amyloid beta, called amyloid beta-42, had also been significantly reduced in the treatment group. The trial failed to show statistically significant improvement based on the CDR-SB score. However, TB006 was shown to be safe and well tolerated over the follow-up. The most common side effect was infusion-related reactions (Bryson 2023).
Following this study, the researchers initiated a long-term open label trial, with once per month TB006 treatment and two-year follow-up. Preliminary results from the open-label trial showed that among 79 people who completed three months of treatment, 47% showed signs of disease reversal or cognitive improvement, and in 28% symptoms did not improve or worsen. Significant adverse events were not reported (Bryson 2023).
There are currently no clinical trials of TB006 enrolling new patients. To provide access to TB006 as an investigational drug, TrueBinding has launched an expanded access (compassionate use) program for interested patients who can cover the cost of their own medication and treatment (TrueBinding 2024a).
Additional Emerging Therapies
The following compounds hold promise, but more research is needed before their potential therapeutic value in Alzheimer’s disease can be deciphered:
- Rapamycin (Cai 2012) – An immunosuppressive drug that also improves removal of cellular debris, including amyloid beta, via enhancing a process called autophagy.
- Secretase inhibitors (used only in preliminary human trials) (Fleisher 2008). These drugs target the enzymes that cleave amyloid precursor protein into amyloid beta fragments. In theory, blocking secretase activity would slow accumulation of amyloid beta.
8 Hormone Replacement Therapy In Alzheimer's Disease
A potential strategy to modulate factors that underlie Alzheimer’s disease is to target age-related depletion of sex hormones. Following menopause, women experience a rapid loss of estrogen and progesterone. Similarly, men experience an age-related loss of testosterone, a condition known as androgen deficiency or hypogonadism. Since sex hormones have fundamental roles in neural health, hormone replacement therapy (HRT) is an intriguing therapeutic consideration in Alzheimer’s disease (Barron 2012).
Pregnenolone
In humans, the steroid hormone cascade begins with pregnenolone, a hormonal derivative of cholesterol. Subsequently, metabolic modification of pregnenolone gives rise to dehydroepiandrosterone (DHEA), which is then converted into estrogens, progesterone, and testosterone (Miller 2002; Luu-The 2010). Aging is associated with a steep decline in the production of pregnenolone and other steroid hormones. French researchers have shown that pregnenolone directly influences acetylcholine release in several key brain regions. They also demonstrated pregnenolone’s ability to promote new nerve growth (Mayo 2003; Mayo 2005).
Dehydroepiandrosterone (DHEA)
DHEA has neuroprotective effects and several studies indicate that patients with Alzheimer’s disease have lower levels of DHEA than those without the disease (Hillen 2000; Polleri 2002; Weill-Engerer 2002). In animal models, DHEA improved memory in rodents that overexpressed amyloid beta (Farr 2004).
Estrogen
Estrogen is an important regulator of neural function. It has been reported to protect neurons from amyloid beta-mediated toxicity as well as to reduce neuronal death in cell culture (Zhang 2003; Bailey 2011). However, the role of estrogen replacement therapy in brain protection is not entirely clear, and may be dependent upon age at initiation (Maki 2012). One research team suggested that estrogen therapy could be beneficial when neurons are still healthy, but might exacerbate Alzheimer’s disease once neurological health is already compromised (Brinton 2005). The Cache County Study reported that Alzheimer’s risk was reduced with long-term HRT (exceeding 10 years) compared to short-term HRT (Zandi 2002), suggesting that early initiation (near menopause) may be an important factor (Carroll 2012; Barron 2012).
Progesterone
Like estrogen, progesterone levels decline during normal aging. Declining progesterone levels are linked with increased amyloid beta, increased NFTs, increased neuron death, and impaired cognition; all of which are associated with Alzheimer’s disease (Barron 2012). Therefore, some scientific evidence suggests that progesterone may be effective for the prevention of degenerative brain diseases including Alzheimer’s disease (Schumacher 2004).
Testosterone
Unlike the sudden drop of female hormones that occurs during menopause, loss of testosterone is gradual in men, with bioavailable levels declining 2-3% annually from approximately 30 years of age (Barron 2012). Several studies have linked low testosterone to increased risk of Alzheimer’s disease in men. In a clinical trial involving 16 male Alzheimer’s patients and 22 healthy controls, 24 weeks of testosterone replacement therapy was associated with improved quality of life compared to placebo among those with Alzheimer’s disease (Lu 2006).
Melatonin
Endogenous melatonin not only helps regulate the sleep-wake cycle, but is a strong antioxidant (Bubenik 2011). Melatonin secretion within the brain declines with age and lower levels are associated with a higher degree of cognitive impairment (Magri 2004). Melatonin concentration is lower in Alzheimer’s patients than in healthy people of the same age (Cardinali 2011). In animal studies, melatonin improved cognitive function and reduced oxidative injury and deposition of amyloid beta (Cheng 2006). Additional studies have confirmed that melatonin protects brain cells from amyloid beta toxicity by impairing amyloid beta generation and slowing the formation of plaque deposits (Wang 2006a). Melatonin has also been shown to reduce tau tangles and amyloid beta toxicity (Srinivasan 2006).
9 Dietary and Lifestyle Management Strategies
Analysis of some dietary patterns indicates that dietary nutrient composition may affect the risk of developing Alzheimer’s disease (Gu 2011)
Mediterranean Diet
The Mediterranean diet has been shown to reduce the risk of Alzheimer’s and other dementias in a host of studies. A recent review found a reduced risk of Alzheimer’s among those whose dietary pattern included a higher intake of fruits, vegetables, fish, nuts, and legumes, as well as a lower intake of meats, high fat dairy, and sweets (Gu 2011). Another recent review of the literature noted a reduced risk of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and mild cognitive impairment, when patients were on a Mediterranean diet (Demarin 2011).
Yet another review found that the Mediterranean diet reduced both the risk of Alzheimer’s disease and the rate of progression from pre-dementia syndromes to overt dementia. The researchers pointed out that the Mediterranean diet largely comprises individual foods (e.g., fish, vegetable oils, non-starchy vegetables, low glycemic index fruits, and red wine), independently proposed as potential protective factors against dementia and pre-dementia (Solfrizzi 2011).
In one study, participants who most closely adhered to the Mediterranean diet, showed 28% lower risk of developing cognitive impairment over a 4.5-year period than those who were less adherent. Also, highly adherent participants with some cognitive impairment at the start of the study experienced 48% lower risk of developing Alzheimer’s disease at follow-up (an average of 4.3 years later) (Scarmeas 2009).
The Mediterranean diet also appears to affect the mortality rate in Alzheimer’s. For example, Alzheimer’s patients whose adherence to the Mediterranean diet was greatest during a study period of 4.4 years were 76% less likely to die than those whose adherence was least. Alzheimer’s patients who adhered to the Mediterranean diet to a moderate degree lived an average 1.3 years longer than those who adhered to the diet to the least degree. Patients who followed the diet very strictly lived, on average, 3.9 years longer (Scarmeas 2007).
Ketogenic Diet
The ketogenic diet, which involves a strict regimen of very high fat, moderate protein, and low carbohydrates, prompts the body to switch from its normal metabolic process of burning glucose to burning ketones. Ketones are substances produced when the body breaks down fat instead of glucose for energy. Initial research is being carried out to investigate the impact of the ketogenic diet on Alzheimer’s development and progression (Jóźwiak 2011). In a transgenic mouse model, 43 days on a ketogenic diet resulted in ketone production and decreased amyloid beta levels (Van der Auwera 2005).
The ketogenic diet can cause adverse side effects (e.g., increased cholesterol levels, kidney stones, and gastroesophageal reflux) (Jóźwiak 2011).
Low-Calorie Diet (Calorie restriction)
Researchers reported that a low-calorie diet reduces the risk of mild cognitive impairment, which is the stage of memory loss between normal aging and overt dementia. Healthy study subjects between ages 70 and 89 were divided into three groups based on their normal daily caloric intake: 600-1526; 1526-2143; and 2143-6000 calories per day. Those in the highest calorie group were almost twice as likely to develop mild cognitive impairment. This association was found to be dose-dependent; the risk increased gradually with the increase in calories (Geda 2012; Pasinetti 2007).
Exercise
Regular exercise is associated with increases in brain-derived neurotrophic factor (BDNF), hippocampal neurogenesis, synaptic plasticity, brain volume, dendritic spines, and vascular function, as well as a reduction in cell death (Cotman 2007; van Praag 2009). Research focusing on Alzheimer’s patients found that those who exercised had reduced brain atrophy compared with those who did not (Burns 2008). As little as three minutes of very intense exercise has been shown to sharply raise BDNF levels, as well as produce a 20% improvement in memory (Winter 2007).
The benefits of exercise may be enhanced by consumption of omega-3 fatty acids and plant polyphenols (van Praag 2009). Exercise and diets rich in omega-3 fatty acids have been shown to help normalize BDNF levels (Gomez-Pinilla 2008; Wu 2004a).
10 Nutrients
Nutritional Interventions Studied in Alzheimer’s
Huperzine A
Derived from the plant Huperzia serrata, huperzine A is an NMDA receptor blocker than can help prevent or reduce glutamate-mediated excitotoxicity (Wang 1999). It can also help block acetylcholinesterase, the enzyme that destroys acetylcholine, which is critical for cognition and memory. This mechanism of action is similar to that of several Alzheimer’s drugs, such as donepezil and galantamine (Sun 1999). Some studies show that huperzine A may penetrate the blood-brain barrier, have greater bioavailability, and have longer duration of action than some pharmaceuticals (Wang 2006b; Bai 2000). Although not all studies on Huperzine show positive effects on cognition (Rafii 2011), a review of previous studies revealed that doses of 300-500 mcg of huperzine A daily significantly improved the standardized cognitive test scores of Alzheimer’s patients, and were slightly safer than some drug alternatives (Wang 2009).
Lion’s Mane (Hericium erinaceus)
Hericium erinaceus (lion’s mane mushroom) is an edible and medicinal mushroom that has been used traditionally in Asia to improve memory (Zhang 2017; Phan 2014; Khan 2013). Some of the major beneficial components found in this mushroom include beta-glucan polysaccharides; erinacine A, C, S; and sesterterpene (Tsai-Teng 2016; Khan 2013). Several laboratory and animal studies reported that compounds from H. erinaceus have lipid-lowering, antioxidant, anti-hypertensive, neuroprotective, anti-tumor, antibacterial, and immune-stimulating effects (Zeng 2018; Zhang 2017; Khan 2013).
In a double-blind placebo-controlled clinical trial, Japanese men and women between 50 and 80 years who had been diagnosed with mild cognitive impairment received 250 mg H. erinaceus tablets containing 96% of the mushroom dry powder three times daily for 16 weeks. After eight weeks, the H. erinaceus group exhibited better cognitive scores than the placebo group, and the improvement continued through the supplementation period (Mori 2009).
In a mouse model of Alzheimer’s disease, 30 days of oral administration of an H. erinaceus extract reduced the production and deposition of amyloid in animals’ brains and supported the growth of brain cells. Longer-term administration, for five months, helped recover cognitive decline in the same study (Tzeng 2018). The benefits of H. erinaceus extracts for cognition are supported by other studies on mouse models of Alzheimer’s disease, which found that the extract improved nerve cell formation, decreased cellular damage, and recovered some of the animals’ behavioral deficits (Tsai-Teng 2016). In another study on mice with Alzheimer’s disease, a H. erinaceus extract increased serum and brain levels of the neurotransmitter acetylcholine, levels of which decline in Alzheimer’s disease (Zhang 2016; Mufson 2008; Kelley 2007). In rats with neuronal injury, an aqueous extract of H. erinaceus promoted the regeneration of peripheral nerves (Wong 2016).
In a different mouse model,supplementation with a H. erinaceus extract blocked inflammatory signaling and reversed the depression-like behavior caused by stress (Chiu 2018). These findings are significant, considering that up to 50% of Alzheimer’s patients experiencedepression (Lyketsos 2002; Chi 2014; Modrego 2010). Benefits have also been observed in healthy mice, in which oral supplementation with a H. erinaceus extract improved recognition memory and neurotransmission in a brain area involved in cognitive function and emotions (Brandalise 2017).
Laboratory studies revealed that extracts or compounds isolated from H. erinaceus support neuronal growth and survival (Zhang 2017). An H. erinaceus water extract was neuroprotective in laboratory experiments and decreased the accumulation of reactive oxygen species inside cells (Zhang 2016).
Benfotiamine
Benfotiamine is a fat-soluble form of vitamin B1 (thiamin) that acts on multiple metabolic pathways, including limiting the production of advanced glycation end products (AGEs). AGEs are metabolic products formed by the non-enzymatic interaction of glucose with proteins and are harmful in the body. Benfotiamine has also shown anti-inflammatory and antioxidant activity. In some preclinical models, benfotiamine has demonstrated inhibition of GSK-3, an enzyme implicated in the pathogenesis of several diseases, including Alzheimer’s disease (Sun 2012; Markova 2017). In animal models of Alzheimer’s disease, administration of benfotiamine has shown promise: animals given benfotiamine have been shown to have decreased levels of amyloid beta and phosphorylated tau proteins, restored neurogenesis, and improved memory (Gibson 2020).
In a 12-month, double-blind, randomized, placebo-controlled trial, 70 participants with mild cognitive impairment or mild Alzheimer’s dementia were give benfotiamine or placebo. At the end of the trial, the participants who took benfotiamine experienced less cognitive decline than those in the placebo group. Specifically, Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores and clinical dementia ratings increased 43% less and 77% less, respectively, for the benfotiamine group than the placebo. In addition, benfotiamine reduced serum levels of AGEs compared with placebo. The effects of benfotiamine appeared to be stronger in participants without the variant ApoE4 gene (Gibson 2020). In a small clinical study in five patients with mild-to-moderate Alzheimer’s disease receiving 300 mg benfotiamine daily for 18 months, participants’ MMSE scores increased by an average of 3.2 points by the end of the trial (Pan 2016).
Lipoic Acid
This potent antioxidant has been shown to reduce inflammation, chelate metals, and increase acetylcholine levels in animal studies (Milad 2010; Holmquist 2007). Although there have been only a few small human studies on lipoic acid in Alzheimer’s, the results hold promise. In one study, nine patients with Alzheimer’s or similar dementias took 600 mg of lipoic acid daily, for an average of 337 days. At the outset of the study, cognitive scores were declining continuously. By the end of the study, they had stabilized (Hager 2001). A second study extended this regime to 43 patients for 48 months and the disease progressed extremely slowly (compared with the typical disease progression rate seen in untreated patients) (Hager 2007).
Acetyl-L-carnitine
Acetyl-L-carnitine (ALC) is an antioxidant that has been shown to correct acetylcholine deficits in animals and protect neurons from amyloid beta by supporting healthy mitochondria (Butterworth 2000; Dhitavat 2005; Virmani 2001). A group of researchers combined ALC with lipoic acid and found they could reverse some mitochondrial decay in aged animals. The same research group conducted a comprehensive review of 21 clinical trials of ALC in cases of mild cognitive impairment and mild Alzheimer’s disease. They found significant benefit in the ALC group compared to placebo (Ames 2004).
ALC has been noted to reduce the effects of high homocysteine levels in mice (e.g., deterioration of blood-brain barrier integrity, increased levels of amyloid beta, neurofibrillary tangle formation, and cognitive dysfunction) (Zhou 2011). Further, a small clinical trial among people with Alzheimer’s disease showed that 3,000 mg of ALC daily resulted in significantly less cognitive deterioration over a 1 year period (Pettegrew 1995). Laboratory studies have found that ALC can reduce amyloid beta neurotoxicity by affecting amyloid precursor protein metabolism (Epis 2008).
Panax ginseng
Ginsenosides, steroid-like compounds in extracts of the plant Panax ginseng (P. ginseng), are believed to be the active chemicals that produce memory benefits (Christensen 2009). A study that tested 200, 400, and 600 mg of P. ginseng on healthy patients without cognitive problems found that 400 mg produced the greatest benefit and boosted memory for 1-6 hours after dosing (Kennedy 2001). When higher dosages were tested on 58 Alzheimer’s disease patients, 4.5 g of P. ginseng given daily over 12 weeks produced gradually increasing improvements, as compared to the 39 control patients whose cognitive abilities declined over the same period, though the improvements faded 12 weeks after discontinuation (Lee 2008).
Vitamins C and E
Vitamins C and E are well known for their antioxidant properties. Several studies have examined their combined potential in reducing the oxidative damage associated with Alzheimer’s disease (Gehin 2006; Shireen 2008). One observational study showed that supplementation with vitamins C (500 mg/day) and E (400 IU/day) was associated with reduced prevalence of Alzheimer’s disease (Boothby 2005). Another team of researchers found that the combination of vitamin C and E was associated with a reduced risk of Alzheimer’s disease, but neither supplement alone conferred substantial protection (Zandi 2004). However, a placebo-controlled clinical trial found that high doses of vitamin E alone, up to 2,000 IU daily, slowed the mental deterioration of Alzheimer’s patients (Grundman 2000), and in an animal model, vitamin C helped reduced amyloid beta aggregation (Cheng 2011).
Deficiencies of vitamin E in Alzheimer’s patients are associated with increased lipid peroxidation (oxidative deterioration of lipids), which appears to increase platelet aggregation (Ciabattoni 2007). Combination therapy with vitamins C and E has been shown to reduce lipid peroxidation in people with mild-to-moderate Alzheimer’s disease (Galbusera 2004). A high intake of vitamins C and E may be associated with reduced incidence of Alzheimer’s in the healthy elderly (Landmark 2006).
One method by which vitamin E might protect Alzheimer’s disease has to do with its relation to apolipoprotein E4 (apoE4). Researchers suspect that, in people with the apoE4 phenotype, impaired antioxidant defense systems in neurons may increase oxidative damage (Mas 2006). Another theory suggests that vitamin E might be able to reduce the oxidative damage caused by large amounts of inducible nitric oxide synthase, a pro-oxidant that has been linked to progression of Alzheimer’s (McCann 2005). Moreover, a recent study suggested that vitamin E may combat amyloid beta-induced oxidative stress, a characteristic of Alzheimer’s disease (Pocernich 2011). (Note: Inducible nitric oxide synthase should not be confused with endothelial nitric oxide synthase that is needed to maintain healthy arterial function.)
Ginkgo biloba
Ginkgo biloba is an antioxidant that may serve as an anti-inflammatory agent, reduce blood clotting, and modulate neurotransmission (Diamond 2000; Perry 1999). In one study, ginkgo was tested on patients with mild-to-moderate Alzheimer’s dementia. The results were inconsistent. However, in a subgroup of those patients with neuropsychiatric symptoms, 120 – 240 mg of ginkgo daily over 26 weeks significantly improved cognitive performance over placebo (Schneider 2005). Another study found that ginkgo inhibited amyloid beta production in the brain (Yao 2004).
Ginkgo, if effectively combined with other brain-supporting nutrients, appears to offer a synergistic cognitive effect, resulting partly from its ability to improve cerebrovascular function (Mashayekh 2011). Research has shown that combining G. biloba with other nutrients such as phosphatidylserine, B vitamins, and vitamin E can deliver cognitive benefits to both animals and humans (Araujo 2008; Kennedy 2007). In addition, a study found that ginkgo extract can rescue neuronal cells from beta amyloid-induced cell death via a mechanism distinct from its antioxidant properties (Aranda-Abreu 2011). Ginkgo also appears to protect against Alzheimer’s disease by inhibiting the formation of amyloid fibrils (Longpré 2006). Finally, a review of six studies found that ginkgo benefits cognition and psychopathological symptoms, with no evidence of negative side effects (Janssen 2010).
Curcumin
Curcumin is derived from the Curcuma longa (turmeric) plant. Many studies have suggested that curcumin may be an effective therapy for Alzheimer’s because it exerts neuroprotective actions through numerous pathways including inhibition of amyloid beta, clearance of existing amyloid beta, anti-inflammatory effects, antioxidant activity, delayed degradation of neurons, and chelation (binding) of copper and iron, among others (Begum 2008; Mishra 2008; Ringman 2005; Walker 2007).
Curcumin has been found to reduce cognitive dysfunction, neural synaptic damage, amyloid plaque deposition, and oxidative damage. It has also been found to modulate the levels of cytokines in brain neurons (Cole 2004; Mishra 2008). The anti-inflammatory effect of curcumin appears to result from a reduction of nuclear factor-kappaB, a nuclear transcription factor that regulates many genes involved in cytokine production (Aggarwal 2004). Curcumin’s ability to chelate toxic metals such as iron and copper and reduce their levels may also help prevent amyloid aggregation (Baum 2004). By inhibiting interaction with heavy metals (e.g., cadmium and lead), curcumin may reduce cerebral deregulation (Mishra 2008). Laboratory studies also suggest that curcumin is more effective at inhibiting accumulation of amyloid beta in animal brains than the over-the-counter NSAIDs ibuprofen and naproxen (Yang 2005). A clinical trial found that doses of regular curcumin ranging from 1 to 4 grams daily were well tolerated and exerted anti-inflammatory effects and possibly reduced amyloid beta aggregation in 27 subjects with probable Alzheimer’s (Baum 2008).
Nutritional Interventions Studied in Cognitive Decline and Dementia
Docosahexaenoic acid
Docosahexaenoic acid (DHA), an omega-3 fatty acid found primarily in fish and fish oil, has been linked to cognitive function (Swanson 2012). DHA constitutes between 30% and 50% of the total fatty acid content of the human brain (Young 2005). It has been shown to reduce amyloid beta secretion (Lukiw 2005) and increase phosphatidylserine levels (Akbar 2005). Studies indicate that omega-3 fatty acids have the ability to inhibit early stages of neurofibrillary tangle formation (Ma 2009) and reduce amyloid plaque development (Amtul 2010). An animal model revealed that fish oil supplementation may combat some of the negative effects of carrying the ApoE4 gene (Kariv-Inbal 2012). In a randomized study involving 485 individuals with age-related cognitive decline, 900 mg of DHA daily for six months resulted in a marked improvement in learning and memory tests (Yurko-Mauro 2010).
One way in which DHA may exert benefits is by working synergistically with other protective compounds, such as carotenoids (Parletta 2013). An 18-month clinical trial investigated the effect of combined treatment with carotenoids and fish oil in 25 participants with Alzheimer’s disease: 12 participants received a xanthophyll carotenoid supplement that provided 10 mg of lutein, 10 mg of meso-zeaxanthin, and 2 mg of zeaxanthin per day; 13 participants received the same carotenoid supplement plus 1 gram of fish oil, providing 430 mg of DHA (docosahexaenoic acid) and 90 mg of EPA (eicosapentaenoic acid) daily. Those receiving the combination of carotenoids plus fish oil experienced greater increases in blood carotenoid levels and less progression of Alzheimer’s disease compared with those receiving carotenoids alone, with reported improvements in memory, sight, and mood.
Vinpocetine
Vinpocetine, derived from the periwinkle plant, has neuroprotective properties and increases cerebral circulation (Szilagyi 2005; Dézsi 2002; Pereira 2003). It also protects against excitotoxicity (Sitges 2005; Adám-Vizi 2000). Vinpocetine has been used as a drug in Eastern Europe for the treatment of age-related memory impairment (Altern Med Rev 2002). In a controlled clinical trial, 10 mg of vinpocetine three times a day improved a variety of measures of cognitive function among subjects with vascular senile cerebral dysfunction (Balestreri 1987). Note: Women who are pregnant or could become pregnant should not use vinpocetine.
Pyrroloquinoline quinone (PQQ)
Pyrroloquinoline quinone (PQQ) is an important nutrient that stimulates the growth of new mitochondria in aging cells, and promotes mitochondrial protection and repair (Chowanadisai 2010; Tao 2007). Mitochondrial decay contributes to many age-related diseases, including Alzheimer’s (Facecchia 2011; Martin 2010). Laboratory studies indicate PQQ may inhibit the development of Alzheimer’s disease (Kim 2010; Liu 2005; Murase 1993; Yamaguchi 1993; Zhang 2009). PQQ protects neurons from amyloid beta and the protein alpha-synuclein, which contributes to neurodegeneration in Parkinson’s disease (Kim 2010; Zhang 2009).
Supplementation with 20 mg per day of PQQ resulted in improvements on tests of higher cognitive function in a group of middle-aged and elderly people (Nakano 2009). These effects were significantly amplified when the subjects also took 300 mg per day of CoQ10.
Phosphatidylserine
Phosphatidylserine (PS) is a naturally occurring component of cell membranes. In a study conducted in Japan on 78 elderly people with mild cognitive impairment, supplementation with PS for six months resulted in significant improvements in memory functions (Kato-Kataoka 2010). In another study, 18 elderly subjects with age-related memory decline took 100 mg of PS 3 times daily for 12 weeks. Tests at 6 and 12 weeks showed cognitive gains compared to baseline measurements (Schreiber 2000). A group of researchers studied the safety and efficacy of phosphatidylserine-containing omega-3 fatty acids (PS-omega-3) in eight elderly patients with memory complaints (Richter 2010). They found that PS-omega-3 had favorable effects on memory functions. Researchers are now finding that phosphatidylserine supplementation works optimally along with docosahexaenoic acid (DHA) (Shyh-Hwa 2012).
Glycerophosphocholine Glycerophosphocholine (GPC) is a structural component of brain cell membranes and a precursor to the neurotransmitter acetylcholine. In Alzheimer’s disease, the concentration of GPC increases in the CSF due to the breakdown of cell membranes during neurodegeneration (Walter 2004). Supplementation with GPC and other nutritive substances like acetyl-L-carnitine, docosahexaenoic acid, α-lipoic acid and phosphatidylserine improves cognitive functions in mice (Suchy 2009). A clinical trial on 261 patients with dementia of the Alzheimer’s type showed improvement in cognitive symptoms with an acetylcholine precursor (Moreno 2003). A larger trial also revealed significant cognitive improvement when patients recovering from stroke were given 1,000 - 1,200 mg of alpha-GPC for 5 months (Barbagallo 1994).
Carotenoids
Carotenoids are red-yellow-orange plant pigments that help prevent photodamage to key components of the system through which plants convert sunlight to energy. They also extend the range of wavelengths of light that plants can utilize for energy production. Carotenoids fall into two groups based on their chemical structures: xanthophylls (eg, astaxanthin, lutein, zeaxanthin) and carotenes (eg, β-carotene). Many carotenoids are present in the diet in healthy, colorful foods such as fruits and vegetables. Some carotenoids have been shown to readily cross the blood-brain barrier and exert neuroprotective effects, including antioxidative and anti-apoptotic actions, in the central nervous system (Park 2020). Additional evidence suggests carotenoids may bind directly to amyloid beta, inhibiting aggregation of the toxic protein in the brain (Lakey-Beitia 2019).
Astaxanthin. Astaxanthin is highly concentrated in some microalgae and gives color to many crustaceans and fish. Like other carotenoids, astaxanthin has strong anti-inflammatory and free radical-scavenging properties (Grimmig 2017; Guedes 2011). Because astaxanthin has been shown to cross the blood-brain barrier, interest in its ability to protect brain tissue from age-related changes has grown. Recent evidence suggests astaxanthin promotes brain plasticity, thereby potentially preventing or ameliorating age-related cognitive impairment (Grimmig 2017; Wu 2015). Many preclinical studies have shown that astaxanthin helps preserve neurological and memory health through a variety of mechanisms (Sifi 2016; Hongo 2020; Han 2019; Wu 2014; Ji 2017; Zhou 2015; Li 2016; Pan 2017; Al-Amin 2019; Taksima 2019; Rahman 2019).
A pilot study in 10 healthy subjects with age-related memory problems demonstrated the potential benefits of astaxanthin supplementation. After 12 weeks using an algae extract providing astaxanthin at 12 mg per day, improvement was noted on cognitive performance tests (Satoh 2009). These results were confirmed in a randomized controlled trial in 96 middle-aged to older adults reporting age-related memory complaints. This trial used 6‒12 mg astaxanthin per day for 12 weeks and found similar improvement in cognitive performance (Katagiri 2012). In another randomized controlled trial, astaxanthin at doses of 6 and 12 mg daily for 12 weeks inhibited the accumulation of oxidized phospholipids in red blood cell membranes of middle-aged and older adults. Abnormal accumulation of these oxidized phospholipids in red blood cells has been observed in people with dementia (Nakagawa 2011). Furthermore, in a randomized controlled trial of 21 healthy participants, astaxanthin combined with sesamin, a lignan found in sesame seeds, was shown to significantly improve psychomotor speed and processing speed compared with placebo after six weeks of treatment (Ito 2018).
Combining astaxanthin with other agents may also be a method for providing neuroprotection. In an in vitro study, the combination of astaxanthin and huperzine A, a cholinesterase inhibitor, resulted in increased cell survival, reduced cell membrane damage, and decreased reactive oxygen species formation in a cell model of neurologic damage (Yang 2020). Additionally, when astaxanthin was combined with another carotenoid, fucoxanthin, in vitro assays showed an increase in multiple measures of neuroprotection, including reduced cell death, increased neuron growth, and higher levels of antioxidant signaling (Alghazwi 2019).
Lutein and zeaxanthin. Lutein and zeaxanthin are two highly pigmented xanthophylls that are found at high concentrations in the retina and macula of humans. Therefore, lutein and zeaxanthin are often referred to as “macular pigments” or “macular carotenoids” (Lima 2016). Given the close anatomic connection between the eyes and central nervous system (Grzybowski 2020), it is not surprising that levels of lutein and zeaxanthin in the macula and blood are significantly associated with cognition. Indeed, these macular carotenoids appear to protect against the development of cognitive impairment (Min 2014; Renzi 2014; Kelly 2015).
Compared to adults with normal cognitive function, those with Alzheimer’s disease have lower serum levels of carotenoids (Mullan 2017). On the other hand, high levels of lutein and zeaxanthin in the blood have been associated with a lower risk of death related to Alzheimer’s disease (Min 2014). In a case-control study, levels of macular pigments in 24 patients with mild cognitive impairment were compared with those of 24 matched controls. Among healthy controls, the level of macular pigment was only associated with visual-spatial and constructional cognitive abilities. However, in those with mild cognitive impairment, macular pigment concentration was associated with global cognition, along with visual-spatial, constructional, verbal, and attentional cognition (Renzi 2014). Furthermore, in a study that followed 1,092 elderly participants without dementia over 10 years, participants with higher lutein concentration at baseline had a 19% lower risk of developing dementia and 24% lower risk of developing Alzheimer’s disease (Feart 2016).
Supplementation with lutein and zeaxanthin may also help slow Alzheimer’s disease-related cognitive decline. In a preliminary uncontrolled trial of 25 patients with Alzheimer’s disease treated with xanthophyll carotenoids either alone or in combination with fish oil, the combination significantly slowed progression of Alzheimer’s disease. Caregivers reported improvements in memory, sight, and mood with treatment (Nolan 2018). In a randomized controlled trial, supplementation with 10 mg lutein, 10 mg meso-zeaxanthin, and 2 mg zeaxanthin resulted in significantly higher serum concentrations of lutein and zeaxanthin as well as improved visual function (Nolan 2015). Furthermore, in healthy individuals with low levels of macular carotenoids, 12 months of supplementation with lutein and zeaxanthin improved memory and cognition compared with placebo (Power 2018).
Although the precise mechanism of action of the macular carotenoids on cognition is unclear, there is evidence that lutein and zeaxanthin have neuroprotective effects similar to those of other carotenoids (Singhrang 2018).
Life Extension Study: Nutrient Complex May Positively Impact Cognitive PerformanceA 2012 study conducted by Life Extension Clinical Research, Inc. assessed the impact of daily dosing of a dietary supplement containing alpha-glyceryl phosphoryl choline (A-GPC), phosphatidylserine, vinpocetine, grape seed extract, wild blueberry extract, ashwagandha extract, and uridine-5’-monophosphate on cognitive performance in forty middle-aged to elderly subjects with subjective memory complaints. An online cognitive assessment tool (Computerized Neuropsychological Test) was used to assess the change in cognitive performance from baseline to day 30 and day 60; the Global Impression Improvement (CGI-I) scale provided an overall clinically determined summary measure. Twenty-nine subjects completed the study with no significant adverse events being reported. Preliminary results revealed a statistically significant improvement in three tests: working Memory (N-back), inspection time, and executive function. Based on the CGI-I Scale, improvement was noted after 30 days and 60 days of product dosing. The study was presented at the Experimental Biology 2012 multidisciplinary scientific conference in San Diego, California April 21-25, 2012. |
Additional Nutritional Support for Cognition
Coffee and Caffeine
A review of several studies revealed that coffee consumption is associated with a reduced risk of Alzheimer’s and Parkinson’s diseases (Butt 2011). Long-term caffeine administration to mice can reduce brain amyloid beta deposition through suppression of beta- and gamma-secretase. An animal model showed that caffeine appeared to synergize with another coffee component to increase blood levels of granulocyte colony-stimulating factor (G-CSF). Both higher G-CSF levels and long-term administration of caffeinated coffee have been shown to enhance working memory (Cao 2011).
Chlorogenic acid, an antioxidant polyphenol present in coffee, has been shown to reduce blood pressure, systemic inflammation, risk of type 2 diabetes, and platelet aggregation (Cao 2011; Montagnana 2012). In one study, when mice with impaired short-term or working memory were given chlorogenic acid, their cognitive impairment was significantly reversed (Kwon 2010). Polyphenol availability varies with how long coffee beans are roasted and the roasting method itself. All roasting destroys some polyphenols, the most important being chlorogenic acid. However, there is a patented roasting process that returns polyphenol content back to the coffee beans allowing for a substantially increased polyphenol content compared to conventionally processed coffee (Zapp 2010). Another excellent source of chlorogenic acid is green coffee extract (Jaiswal 2010).
Green Tea
The flavonoids in green tea, known as catechins, have been shown to possess metal-chelating (binding) properties, as well as antioxidant and anti-inflammatory effects (Mandel 2006). Animal studies have demonstrated that the main flavonoid in green tea, epigallocatechin gallate (EGCG), along with other tea catechins, can decrease levels of amyloid beta in the brain (Rezai-Zadeh 2005), and suppress amyloid beta-induced cognitive dysfunction and neurotoxicity (Haque 2008; Kim 2009; Rezai-Zadeh 2008). Studies propose that green tea catechins also act as modulators of neuronal signaling and metabolism, cell survival-and-death genes, and mitochondrial function. Recently, population based studies have determined that intake of catechins in both green and black tea may reduce the incidence of Alzheimer’s disease and dementia (Mandel 2011).
Resveratrol
Resveratrol – a polyphenol found in Japanese knotweed, red wine, and grapes – has been shown to reduce amyloid beta levels, neurotoxicity, cell death, and degeneration of the hippocampus, as well as prevent learning impairment (Kim 2007). Several studies indicate that moderate consumption of red wine, in particular, is associated with a lower incidence of dementia and Alzheimer’s disease (Vingtdeux 2008). Red wine also contains many phenolic antioxidant compounds that, research suggests, impede the pathological progress of Alzheimer’s disease (Ho 2009). It has also been observed that stilbenoids – derivatives of resveratrol – lower amyloid beta peptide aggregation in Alzheimer’s models (Richard 2011). Resveratrol has been shown to selectively neutralize detrimental clumps of amyloid peptides while leaving benign peptides intact as well (Ladiwala 2010).
Grape Seed Extract
Grape seed extract contains potent antioxidants called proanthocyanidins (Shi 2003). In laboratory experiments, animal neurons were treated with grape seed extract before being exposed to amyloid beta. Unlike the untreated neurons that readily accumulated free radicals and subsequently died, the cells treated with grape seed extract were significantly protected (Li 2004). In another animal study, administering grape seed polyphenols reduced amyloid beta aggregation in the brain and slowed Alzheimer’s disease-like cognitive impairment (Wang 2008).
Magnesium
Magnesium is involved in the functioning of NMDA-type glutamate receptors, which are integral to memory processing (Bardgett 2005). Studies have found that imbalance of serum magnesium levels causes cognitive impairment (Corsonello 2001; Barbagallo 2011). Recently, scientists have discovered that a specially formulated magnesium compound called magnesium-L-threonate (MgT) boosts brain levels of magnesium more efficiently than other forms of magnesium. These higher brain levels of magnesium improved synaptic signaling, which is essential for proper neuronal and cognitive function, as well as enhanced long-term learning and memory. Testing of MgT on animals showed a substantial improvement in memory, especially long-term memory (Slutsky 2010).
B Vitamins
High homocysteine levels, along with low levels of B vitamins (e.g., folate, vitamin B12, and vitamin B6), have been associated with Alzheimer’s disease and mild cognitive impairment (Quadri 2005; Ravaglia 2005; Tucker 2005).
- Vitamin B12. In a study evaluating levels of vitamin B12 in patients with either Alzheimer’s disease or another type of dementia, researchers found that lower B12 levels were linked to greater cognitive deterioration (Engelborghs 2004). A population-based longitudinal study of people 75 or older without dementia found that those with low levels of vitamin B12 or folate had twice the risk of developing Alzheimer’s disease over a three-year period (Wang 2001).
- Vitamin B6. A study found that Alzheimer’s patients after age 60 consumed a significantly lower amount of vitamin B6 compared to control subjects (Mizrahi 2003). In addition, low vitamin B6 levels were associated with elevated numbers of lesions in the brains of patients with Alzheimer’s disease (Mulder 2005).
- Folate. Folate is needed for DNA synthesis (Hinterberger 2012). In a study including 30 subjects with Alzheimer’s disease, levels of folate in cerebrospinal fluid were significantly lower in patients with late-onset Alzheimer’s disease (Serot 2001). Another longitudinal analysis of people aged 70 to 79 years found that those with either high levels of homocysteine or low levels of folate had impaired cognitive function. The link to cognitive impairment was strongest for low folate levels, leading researchers to suggest that folate might reduce the risk of cognitive decline (Kado 2005).
- Niacin. A study of more than 6,000 people, conducted between 1993 and 2002, found that high levels of dietary niacin (vitamin B3) protected against Alzheimer’s disease. The authors researched the dietary habits of initially healthy people aged 65 years or older. As the study progressed, some participants developed Alzheimer’s disease and some remained healthy. Subjects with the highest intake of niacin had a 70% reduction in risk of cognitive decline (Morris 2004).
Vitamin D
The wide distribution of vitamin D receptors in the brain may be evidence for vitamin D’s importance in neurological function (Eyles 2005). Studies show that clearance of amyloid beta across the blood-brain barrier is promoted by adequate levels of vitamin D. Animal tests showed 1.3 times greater rate of amyloid beta elimination with vitamin D supplementation, pointing to a potential preventive effect against Alzheimer’s disease (Ito 2011). Among nearly 500 women followed for 7 years, those in the highest quintile (1/5th) for vitamin D intake had a more than 75% reduction in risk of developing Alzheimer’s disease compared to those in the lowest quintile (Annweiler 2012).
Coenzyme Q10
Coenzyme Q10 (CoQ10) has been found to improve outcomes in several neurodegenerative disorders involving loss of mitochondrial function (Galpern 2007; Manacuso 2010).
Studies have shown that levels of CoQ10 are altered in Alzheimer’s disease (Dhanasekaran 2005), and supplementation has been suggested as part of an integrated approach to improve mitochondrial function in Alzheimer’s disease (Kidd 2005).
In one animal study, CoQ10 counteracted mitochondrial deficiencies in rats that had been treated with amyloid beta (Moreira 2005), while in another experiment CoQ10 reduced the overproduction of amyloid beta (Yang 2008). Coenzyme Q10 was also shown to destabilize amyloid plaques in laboratory studies (Ono 2005).
Several clinical trials have evaluated the effects of synthetic CoQ10 analogs in Alzheimer’s patients and shown good results. For example, a trial comparing tacrine, a pharmaceutical acetylcholinesterase inhibitor, to a CoQ10 analog among 203 Alzheimer’s patients showed the CoQ10 analog was associated greater improvements on some standardized cognitive assessments (Gutzmann 2002). Another trial revealed dose-dependent improvements on cognitive assessments in Alzheimer’s patients receiving a CoQ10 analog compared to placebo. This trial also showed the CoQ10 analog to be safe and well tolerated (Gutzmann 1998). Similarly, in a trial conducted on 102 Alzheimer’s patients, a CoQ10 analog improved memory, attention, and behavior compared to placebo (Senin 1992).
N-acetylcysteine
N-acetylcysteine (NAC) is a precursor to glutathione, a powerful scavenger of free radicals in the body (Forman 2009; Arakawa 2007). Glutathione deficiency has been associated with a number of neurodegenerative diseases (Pocernich 2000). One study showed that NAC significantly increased glutathione levels and reduced oxidative stress in rodents treated with a known free radical–producing agent (Pocernich 2000). Another study showed that glutathione-deficient mice were more vulnerable to neuronal damage from amyloid beta (Crack 2006). An animal model of Alzheimer’s found that NAC alleviated oxidative damage and cognitive decline (Tchantchou 2005).
Ashwagandha
Ashwagandha or Withania somnifera is a plant used in India to treat a wide range of age-related disorders (Ven Murthy 2010). A 2012 study using an animal model of Alzheimer’s disease found that ashwagandha reversed accumulation of amyloid peptides and improved behavioral deficits (Sehgal 2012). Laboratory studies have shown that ashwagandha can regenerate neurites (i.e., projections from nerve cells) and reconstruct synapses in severely damaged neurons (Kuboyama 2005). In addition to its neuroprotective benefits, ashwagandha has been shown to mimic the action of the Alzheimer’s drug donepezil, an acetylcholinesterase inhibitor (Choudhary 2004).
Blueberry Extract
In 2005, scientists noted that the polyphenols present in blueberries reversed the cognitive and motor deficits caused by aging (Lau 2005). Blueberry extract stimulates neurogenesis and enhances neuronal plasticity (adaptability) in the hippocampus, the region of the brain chiefly affected by Alzheimer’s disease (Casadesus 2004). In one study where researchers analyzed fruits and vegetables for their antioxidant capability, blueberries came out on top, scoring highest for its capacity to neutralize free radicals (Wu 2004b).
Luteolin
Luteolin, a flavonoid found in fruits and vegetables (e.g., green peppers, carrots, and celery), exhibited a protective effect against Alzheimer’s disease in early research. When luteolin was administered to mice with Alzheimer’s disease, there was a significant reduction in levels of amyloid beta. These mice also exhibited a reduction in the activity of glycogen synthase kinase 3, an enzyme that has been implicated in the development of amyloid beta and neurofibrillary tangles (Rezai-Zadeh 2009).
Multi-Nutrient Combinations & Comprehensive Interventions
Alzheimer’s disease is a complex condition with various contributing factors. As with cardiovascular disease—for which it has become clear over the years that effective prevention and treatment requires a multi-faceted approach—evidence continues to accumulate that Alzheimer’s disease necessitates a similarly comprehensive strategy (Singhaarachchi 2024; Mayo 2024; Yarns 2022).
A systematic review of 32 randomized controlled trials reported that multi-nutrient interventions have shown some promising effects in Alzheimer’s disease, but the evidence remains inconclusive (Moreira 2020). It is important to understand that studies evaluating multicomponent interventions have used a range of therapies and differing methods, not all of which have been rigorous; therefore, more studies are needed.
The benefits of multi-nutrient supplements in Alzheimer’s disease are thought to be augmented by a comprehensive diet and lifestyle approach intended to support brain function. A randomized controlled trial in 51 patients with mild cognitive impairment or early-stage dementia due to Alzheimer’s disease, whose average age was 73.5 years, compared an intensive 20-week diet and lifestyle intervention to usual care (control). Both groups underwent standard of care management by their own neurologist. The intervention included:
- A whole-foods vegan diet, high in complex carbohydrates and low in refined carbohydrates, harmful fats, and sweeteners, with all meals and snacks provided
- One hour per day of stress management training (meditation, stretching, yoga-like exercises, breathing exercises, and other stress-relieving activities) supervised by a certified stress management specialist
- One hour three times per week of group support, including memory exercises, supervised by a licensed mental health professional
- Twelve hours of counseling per week by teleconference to reinforce lifestyle aspects of the program
- Daily nutrient supplements providing 1,680 mg omega-3 fatty acids, 800 mg curcumin, 200 mg CoQ10, 1,000 mg vitamin C, 500 mcg vitamin B12, 144 mg magnesium L-threonate, 2 grams lion’s mane mushroom, a probiotic, and a basic multivitamin/mineral supplement without iron
After 20 weeks, relative to the control group, those in the intervention group improved in multiple measures of clinical function, dementia, and cognition, including Clinical Global Impression of Change and Clinical Dementia Ratings. A blood biomarker strongly suggestive of Alzheimer’s disease, amyloid-beta 42/40 ratio, improved in the intervention group but worsened slightly in the control group. Improvements in the microbiomes of the intervention group were also noted (Ornish 2024).
Another randomized controlled trial was conducted in 46 patients, aged 60 to 85 years, with a diagnosis of mild cognitive impairment or Alzheimer’s disease. All of the participants had amyloid pathology confirmed by PET scan. The eight-week trial had three groups: a control group, a group that received dietary supplements only, and a group that received a multifactor intervention plus dietary supplements. The multifactor program included managing cardiometabolic risk factors, cognitive training, physical exercise, nutritional guidance, and a motivational intervention. The nutritional supplement was administered as a prepackaged drink that delivered low-potency vitamins and minerals, omega-3 fatty acids (EPA and DHA), medium-chain triglycerides, and phosphatidylserine. In the multifactor intervention group, there was improvement in a standardized measure of neuropsychological status, as well as in microbiome health, compared with nutritional supplementation alone or usual treatment (Lee 2023). The dosages of the individual ingredients in the formula used in this study were not reported.
One of the most-studied multi-nutrient supplements for Alzheimer’s disease prevention and treatment is called Souvenaid, or Fortasyn Connect. It contains 625 mg uridine monophosphate, 400 mg choline, 300 mg EPA, 1,200 mg DHA, 106 mg phospholipids, 80 mg vitamin C, 40 mg vitamin E, 1 mg B6, 400 mcg B9, 3 mcg B12, and 60 mcg selenium. One randomized placebo-controlled trial included 311 subjects with mild cognitive impairment due to early Alzheimer’s disease; after two years, those receiving the supplement had less worsening in their clinical dementia rating and less change in brain structure, but no improvement in cognitive performance (Soininen 2017). However, a second report of findings from 162 participants who remained in the trial for three years showed those receiving the supplement had less decline in all measures related to cognitive performance, clinical function, brain atrophy, and disease progression compared with those receiving placebo, suggesting these benefits become evident over long periods of time. This trial is expected to continue until an endpoint of six years (Soininen 2021; Hendrix 2023). As of mid-2024, Souvenaid is available in the United Kingdom, Australia, Brazil, and several European countries, but not in North America.
A preliminary uncontrolled study in 14 people with early-stage Alzheimer’s disease examined the effect of a daily multi-nutrient supplement providing 400 mcg folic acid, 6 mcg vitamin B12, 30 IU vitamin E (form not specified), 400 mg S-adenosylmethionine (SAM-e), 600 mg NAC, and 500 mg acetyl-L-carnitine per day; after 12 months, dementia rating scores were found to have improved and performance on cognitive and clinical function tests were stable or improved (Chan 2009). In a randomized controlled trial that included 106 participants with Alzheimer’s disease, those given the same multi-nutrient supplement for three months showed improvement on a test of executive function and on the Dementia Rating Scale compared with those given placebo (Remington 2015).
A randomized controlled trial tested a daily multi-nutrient supplement in 77 participants with mild-to-moderate Alzheimer’s disease. The multi-nutrient formula used in this study included 1 gram fish oil (including 500 mg DHA and 150 mg EPA), 22 mg carotenoids (10 mg lutein, 10 mg meso-zeaxanthin, and 2 mg zeaxanthin), and 15 mg d-alpha tocopherol. Participants took the multi-nutrient formula or placebo for 12 months. The supplemented group showed improvement on standard measures of Alzheimer’s disease severity (mood and memory) and marked improvement in memory as reported by caregivers (Nolan 2022).
Another randomized placebo-controlled trial involving 60 patients with mild-to-moderate Alzheimer’s disease tested the effects of a supplement containing 12.35 grams L-serine, 1 gram nicotinamide riboside, 2.55 grams N-acetylcysteine (NAC), and 3.73 grams L-carnitine tartrate. The supplement was taken daily for 28 days, then twice daily for an additional 56 days (total of 84 days). After 84 days, cognitive function scores had improved by 29% in the supplement group versus only 14% in the placebo group; however, the difference between groups was not statistically significant, partly due to the small size of the trial. Further analyzing the data, the researchers found the difference in cognitive improvement between the supplement and placebo groups was significant in a subset of participants with worse baseline scores. In addition, those who received the supplement showed increases in volume and thickness of brain regions affected early in Alzheimer’s disease, and in blood levels of NAD+ and glutathione (Yulug 2023).
Multi-faceted programs may also help protect people without Alzheimer’s disease but at high risk. In a randomized controlled trial, 1,190 participants, aged 60 to 77 years, with an increased risk of dementia and average or slightly below expected-for-age cognitive function received either a two-year multifactor intervention or general health advice alone (control). The intervention included individual and group nutritional guidance, strength training and aerobic exercise, individual and group cognitive training, and management of vascular risk factors (hypertension, diabetes, and abnormal blood lipid levels). At the end of the trial, those who received the comprehensive intervention performed better on a neuropsychological battery of tests, regardless of their baseline demographics, cardiovascular and cognitive health, or APOE4 carrier status (Ngandu 2015; Rosenberg 2018; Solomon 2017). After an additional follow-up period averaging 7.4 years, the risks of coronary events, strokes, and transient ischemic attacks (TIAs) were found to be lower in the intervention group than the control group (Lehtisalo 2022). Based on these findings, an international network of researchers is currently collaborating to investigate the applicability of this comprehensive approach to dementia prevention in more than 20 other countries, including the United States (Kivipelto 2020). Another randomized controlled trial in 172 elderly participants at increased risk of dementia found a two-year intervention including health coaching, regular nursing care, and personalized risk reduction strategies was more effective than health education alone for improving cognition, reducing dementia risk factors, and increasing quality of life (Yaffe 2024).
Wild Green Oat Extract
Extracts of oat (Avena sativa L.) contain bioactive components that exert antioxidant and anti-inflammatory properties (Lee 2015). Oat extracts contain flavonoids, saponins, and compounds unique to oat species, avenanthramides (Wong 2012; Dimpfel 2011).
Increased monoamine oxidase B (MAO-B) activity decreases dopamine levels in the brain and increases oxidative stress in neurons (Nagatsu 2006; Mallajosyula 2009). Analyses of brain tissue from deceased individuals with Alzheimer's disease was found to contain up to three times the amount of MAO-B activity than brain tissue of healthy, age-matched controls (Saura 1994; Jossan 1991).
Monoamine oxidase inhibitors are considered promising therapeutic targets for the treatment of Alzheimer's disease because of their ability to reduce accumulation of beta amyloid and improve cognition and memory deficits (Cai 2014; Delumeau 1994; Finali 1991). Wild green oat extract is able to inhibit MAO-B activity (Wong 2012; Moccetti 2006).
Elderly patients with mild cognitive impairment performed substantially better on cognition tests after a single 1600 mg dose of wild green oat extract (Berry 2011). Healthy, middle-aged adults participating in a double-blind placebo-controlled trial improved their performance on multiple cognitive tests after a single 800 mg dose of wild green oat extract (Kennedy 2015).
Nicotinamide Riboside
Nicotinamide riboside is a source of vitamin B3 that the body uses as a precursor for nicotinamide adenine dinucleotide (NAD), a molecule involved in a range of biological processes. NAD+, a biologically active forms of NAD, is necessary for the activation of sirtuins, proteins that modulate cellular metabolism and DNA transcription (Houtkooper 2010; Chi 2013; Imai 2014). NAD+-dependent sirtuins appear to be involved in such fundamental cellular activities as energy metabolism, DNA damage response, stress resistance, proliferation and differentiation, survival, and aging, and in animal research have been shown to modulate brain connectivity and memory formation (Gao 2010; Srivastava 2016). NAD+ levels decrease with age, which may cause dysfunction in cell nuclei and mitochondria, ultimately contributing to a range of age-related disorders, including cognitive decline and Alzheimer’s disease (Srivastava 2016; Imai 2014). In experimental cellular models of neurodegenerative processes, NAD, NAD+, and nicotinamide riboside have prevented the breakdown of neurons and neuronal connections (Deleglise 2013; Sasaki 2006). Restoration of NAD+ with supplemental nicotinamide riboside has been shown to reverse age-related cellular dysfunction, which contributes to many neurodegenerative diseases, while models of Alzheimer’s disease indicate nicotinamide riboside may be neuroprotective (Imai 2014; Canto 2012; Chi 2013).
In a six-month controlled trial in 26 individuals with probable Alzheimer’s disease, those who received the NADH form of nicotinamide adenine dinucleotide had no progression in cognitive decline and significantly better scores on a dementia rating scale compared with the placebo group (Demarin 2004). In rodents, NADH administration in older animals resulted in improved performance on cognitive tests (Rex 2004). In a mouse model of Alzheimer’s disease, three months of nicotinamide riboside supplementation led to increased brain levels of NAD+, prevented cognitive decline, and reduced levels of neuron damaging amyloid-beta proteins (Gong 2013).
Colostrinin (Proline-rich peptide complex)
Colostrum—the first breast milk secreted after childbirth—is known for its high levels of antibodies and other factors with immune-activating effects (Godhia 2013). Findings from preclinical and clinical studies suggest colostrinin, a proline-rich polypeptide complex in colostrum, may help prevent the progression of Alzheimer’s disease (Janusz 2013; Stewart 2008). A number of studies have found a range of possible mechanisms for colostrinin’s beneficial effects, including modulating immune activity; preventing oxidative stress, including oxidative damage to DNA; anti-inflammatory activity; inhibiting overproduction of nitric oxide; and decreasing age-related mitochondrial dysfunction (Boldogh 2008; Janusz 2010; Zablocka 2010; Zablocka 2012; Bacsi 2007; Bacsi 2006).
A double-blind placebo-controlled trial compared colostrinin to placebo in 105 subjects with mild-to-moderate Alzheimer’s disease. The colostrinin group received 100 micrograms colostrinin every other day for three weeks, followed by two weeks with no treatment, for three 5-week cycles. After the first 15-week period, all subjects received colostrinin for a second 15-week treatment cycle. Colostrinin treatment had a stabilizing effect on cognitive function and ability to perform activities of daily living. Participants with mild cognitive impairment responded better to treatment than those with more advanced decline (Bilikiewicz 2004). Another trial used the same dosing schedule for 16 to 28 months in 33 Alzheimer’s patients and found it resulted in stabilization or improvement in health status (Leszek 2002). An earlier double-blind placebo-controlled trial was conducted in 46 patients with Alzheimer’s disease and mild-to-moderate dementia. Subjects received either 100 micrograms colostrinin, 100 micrograms selenium, or placebo every other day in three-week treatment cycles, followed by two weeks of no treatment. Eight of 15 colostrinin patients improved, while seven of them experienced stabilization of their condition; in contrast, none of the patients in the selenium or placebo groups improved (Leszek 1999). Studies reported colostrinin was well tolerated with mild side effects that passed quickly (Leszek 2002; Leszek 1999).
Studies in which cultured nerve cells were treated with colostrinin or a nanopeptide fragment of colostrinin have demonstrated their potential to disrupt amyloid beta fibrils and prevent further accumulation and neurotoxic effects of amyloid beta (Janusz 2009; Douraghi-Zadeh 2009; Bourhim 2007; Schuster 2005).
Cannabidiol
The phytocannabinoid cannabidiol (commonly referred to as CBD) has been shown in preclinical studies to possess neuroprotective, anti-inflammatory, and antioxidant activity, as well as to prevent the accumulation of amyloid beta and hyperphosphorylated tau protein (Karl 2017). In addition, CBD may block the amyloid beta-mediated hyperphosphorylation of GSK-3 (Li 2020). In a mouse model of early onset familial Alzheimer’s disease, treatment with CBD improved disease symptoms and cognitive function. CBD also increased expression of IL-33 and TREM2, two proteins involved in modulating neuroinflammation and synaptic plasticity and which may be dysregulated in Alzheimer’s disease (Khodadadi 2021).
2024
- Oct: Updated section on monoclonal antibodies (mABs) in Medical Treatment
- Oct: Updated sections on inflammation & herpes and Alzheimer’s/dementia risk in Theories of Alzheimer’s Disease
- Oct: Replaced section on Medical Treatment
- Oct: Added section on TB006 to Novel and Emerging Approaches
- Jul: Updated section on multi-nutrient combinations & comprehensive interventions under Nutrients
- Jun: Added section on klotho to Novel and Emerging Approaches
- Feb: Updated section on multi-nutrient combinations in Nutrients
2023
- Aug: Added section on herpesviruses and Alzheimer’s/dementia risk to Theories of Alzheimer’s Disease
2021
- May: Added section on cannabidiol to Nutrients
- May: Added section on benfotiamine to Nutrients
- May: Added section on anti-apoE4 immunotherapy to Additional Pharmacologic Therapies
- May: Added section on type 3 diabetes to Risk Factors for Alzheimer’s Disease
- May: Added section on exposure to aluminum to Theories of Alzheimer’s Disease
- May: Updated section on infections in Theories of Alzheimer’s Disease
2012
- Aug: Comprehensive update & review
Disclaimer and Safety Information
This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.
The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.
[No authors listed]. Vinpocetine Monograph. Altern Med Rev. 2002;7(3): 240-3. Available at: http://www.altmedrev.com/publications/7/3/240.pdf Accessed 7/25/2012.
AAN. American Academy of Neurology. Monoclonal Antibodies for Alzheimer's Resources. Accessed 9/5/2024, https://www.aan.com/tools-resources/monoclonal-antibodies-alzheimers
Abraham CR, Li A. Aging-suppressor Klotho: Prospects in diagnostics and therapeutics. Ageing Res Rev. Dec 2022;82:101766. doi:10.1016/j.arr.2022.101766. https://pubmed.ncbi.nlm.nih.gov/36283617/
Adám-Vizi V. “Neuroprotective Effect of Sodium Channel Blockers in Ischemia: The Pathomechanism of Early Ischemic Dysfunction” [in Hungarian]. Orv Hetil. 141.23 (2000): 1279-86.
Adityanjee, Munshi KR, Thampy A. The syndrome of irreversible lithium-effectuated neurotoxicity. Clinical neuropharmacology. Jan-Feb 2005;28(1):38-49.
Aggarwal BB, et al. “Suppression of the Nuclear Factor-KappaB Activation Pathway by Spice-Derived Phytochemicals: Reasoning for Seasoning.” Ann N Y Acad Sci. 1030 (2004): 434-41.
Akbar M, et al. “Docosahexaenoic Acid: A Positive Modulator of Akt Signaling in Neuronal Survival.” Proc Natl Acad Sci USA. 102.31 (2005): 10858-63.
Al-Amin MM, Mahmud W, Pervin MS, Ridwanul Islam SM, Ashikur Rahman M, Zinchenko A. Astaxanthin ameliorates scopolamine-induced spatial memory deficit via reduced cortical-striato-hippocampal oxidative stress. Brain research. 2019;1710:74-81.
Alghazwi M, Smid S, Musgrave I, Zhang W. In vitro studies of the neuroprotective activities of astaxanthin and fucoxanthin against amyloid beta (Abeta1-42) toxicity and aggregation. Neurochemistry international. 2019;124:215-224.
Alkadhi K and Eriksen J. The complex and multifactorial nature of Alzheimer's disease. Curr Neuropharmacol. 2011 Dec;9(4):586.
Alvarez G, Munoz-Montano JR, Satrustegui J, Avila J, Bogonez E, Diaz-Nido J. Regulation of tau phosphorylation and protection against beta-amyloid-induced neurodegeneration by lithium. Possible implications for Alzheimer's disease. Bipolar disorders.Jun 2002;4(3):153-165.
Alzheimer’s Association. Diagnosis of Alzheimer’s Disease and Dementia. 2012. Available at: http://www.alz.org/alzheimers_disease_diagnosis.asp. Accessed May 24, 2012a.
Alzheimer’s Association. Risk Factors. 2012. Available at: http://www.alz.org/alzheimers_disease_causes_risk_factors.asp?gclid=CLyKuavN8bACFQeCnQoduQNh-Q. Accessed June 28, 2012b.
Ames BN, et al. “Delaying the Mitochondrial Decay of Aging with Acetylcarnitine.” Ann N Y Acad Sci. 1033 (2004): 108-16.
Amtul Z, et al. “Structural Insight Into the Differential Effects of Omega-3 and Omega-6 Fatty Acids on the Production of Abeta Peptides and Amyloid Plaques.” J Biol Chem. 2011 Feb;286(8):6100-6107 .
Angelucci F, Cechova K, Amlerova J, Hort J. Antibiotics, gut microbiota, and Alzheimer's disease. J Neuroinflammation. 2019;16(1):108.
Annweiler C, Rolland Y, Schott AM, et al. Higher Vitamin D Dietary Intake Is Associated with Lower Risk of Alzheimer's Disease: A 7-Year Follow-Up. [In Eng] J Gerontol A Biol Sci Med Sci. 2012 Apr 13;
Aprahamian I, Santos FS, dos Santos B, et al. Long-term, low-dose lithium treatment does not impair renal function in the elderly: a 2-year randomized, placebo-controlled trial followed by single-blind extension. The Journal of clinical psychiatry.Jul 2014;75(7):e672-678.
Arakawa M and Ito Y. “N-acetylcysteine and Neurodegenerative Diseases: Basic and Clinical Pharmacology.” Cerebellum. (2007):1-7. Epub ahead of print.
Aranda-Abreu GE, et al. “Rehabilitating a Brain with Alzheimer’s: A Proposal.” Clin Interv Aging. 6 (2011): 53-9.
Araujo JA, et al. “Improvement of Short-Term Memory Performance in Aged Beagles by a Nutraceutical Supplement Containing Phosphatidylserine, Ginkgo biloba, Vitamin E, and Pyridoxine.” Can Vet J. 49.4 (2008): 379-85.
Ardebili SM, Yeghaneh T, Gharesouran J, et al. Genetic association of TNF-α-308 G/A and -863 C/A polymorphisms with late onset Alzheimer’s disease in Azeri Turk population of Iran.” J Res Med Sci. 16.8 (2011): 1006-1013.
Azab AN, Shnaider A, Osher Y, Wang D, Bersudsky Y, Belmaker RH. Lithium nephrotoxicity. International journal of bipolar disorders.Dec 2015;3(1):28.
Bacsi A, Aguilera-Aguirre L, German P, Kruzel ML, Boldogh I. Colostrinin decreases spontaneous and induced mutation frequencies at the hprt locus in Chinese hamster V79 cells. Journal of experimental therapeutics & oncology.2006;5(4):249-259.
Bacsi A, Woodberry M, Kruzel ML, Boldogh I. Colostrinin delays the onset of proliferative senescence of diploid murine fibroblast cells. Neuropeptides.Apr 2007;41(2):93-101.
Bai DL, et al. “Huperzine A: A Potential Therapeutic Agent for Treatment of Alzheimer’s Disease.” Curr Med Chem. 7.3 (2000): 355-74.
Bailey ME, Wang AC, Hao J, et al. teractive effects of age and estrogen on cortical neurons: implications for cognitive aging. Neuroscience. 2011 Sep 15;191:148-58.
Balestreri R, Fontana L, Astengo F. A double-blind placebo controlled evaluation of the safety and efficacy of vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfunction. J Am Geriatr Soc. 1987 May;35(5):425-30.
Baloyannis SJ, and Baloyannis IS. The vascular factor in Alzheimer's disease: A study in Golgi technique and electron microscopy. J Neurol Sci. 2012 Aug 2. [Epub ahead of print]
Barbagallo M, et al. “Altered Ionised Magnesium Levels in Mild-to-Moderate Alzheimer’s Disease.” Magnes Res. 24.3 (2011): S115-21.
Barbagallo Sangiorgi G, et al. "Alpha-Glycerophosphocholine in the mental recovery of cerebral ischemic attacks." An Italian multicenter clinical trial. Ann NY Acad Sci 1994; 717:253-69.
Bardgett ME, et al. “Magnesium Deficiency Impairs Fear Conditioning in Mice.” Brain Res. 1038.1 (2005): 100-6.
Barron AM, Pike CJ. “Sex hormones, aging, and Alzheimer’s disease.” Front Biosci (Elite Ed). 2012 Jan 1;4:976-97.
Baum L, et al. “Curcumin Interaction with Copper and Iron Suggests One Possible Mechanism of Action in Alzheimer’s Disease Animal Models.” J Alzheimers Dis. 6.4 (2004): 367-77.
Baum L, Lam CW, Cheung SK, et al. Six-Month Randomized, Placebo-Controlled, Double-Blind, Pilot Clinical Trial of Curcumin in Patients with Alzheimer Disease. [In eng] J Clin Psychopharmacol. 2008 Feb; 28(1): 110-3.
Begum AN, et al. “Curcumin Structure-Function, Bioavailability, and Efficacy in Models of Neuroinflammation and Alzheimer’s Disease.” J Pharmacol Exp Ther. 326.1 (2008): 196-208.
Belluck P, Robbins R. Three F.D.A. Advisers Resign Over Agency's Approval of Alzheimer's Drug. The New York Times [online]. Updated 9/2/2021. Accessed 9/16/2024, https://www.nytimes.com/2021/06/10/health/aduhelm-fda-resign-alzheimers.html?
Bendlin BB. Antidiabetic therapies and Alzheimer disease. Dialogues in clinical neuroscience. 2019;21(1): 83-91.
Berry NM, Robinson MJ, Bryan J, Buckley JD, Murphy KJ, Howe PR. Acute effects of an Avena sativa herb extract on responses to the Stroop Color-Word test. Journal of alternative and complementary medicine.Jul 2011;17(7):635-637.
Beydoun MA, et al. Clinical and Bacterial Markers of Periodontitis and Their Association with Incident All-Cause and Alzheimer's Disease Dementia in a Large National Survey. J Alzheimers Dis. 2020;75(1): 157-172.
Biasutti M, Dufour N, Ferroud C, et al. “Cost-Effectiveness of Magnetic Resonance Imaging with a New Contrast Agent for the Early Diagnosis of Alzheimer’s Disease.” PLoS One. 7.4 (2012): e35559.
Bilikiewicz A, Gaus W. Colostrinin (a naturally occurring, proline-rich, polypeptide mixture) in the treatment of Alzheimer's disease. Journal of Alzheimer's disease: JAD.Feb 2004;6(1):17-26.
Blum S, et al. “Memory after Silent Stroke: Hippocampus and Infarcts Both Matter.” Neurology. 78.1 (2012): 38-46.
Boldogh I, Kruzel ML. Colostrinin: an oxidative stress modulator for prevention and treatment of age-related disorders. Journal of Alzheimer's disease: JAD.Apr 2008;13(3):303-321.
Boothby LA, Doering PL. “Vitamin C and vitamin E for Alzheimer’s disease.” Ann Pharmacother. 39.12 (2005):2073-80.
Bourhim M, Kruzel M, Srikrishnan T, Nicotera T. Linear quantitation of Abeta aggregation using Thioflavin T: reduction in fibril formation by colostrinin. Journal of neuroscience methods.Mar 15 2007;160(2):264-268.
Boza-Serrano A, Vrillon A, Minta K, et al. Galectin-3 is elevated in CSF and is associated with Abeta deposits and tau aggregates in brain tissue in Alzheimer's disease. Acta Neuropathol. Nov 2022;144(5):843-859. doi:10.1007/s00401-022-02469-6. https://pubmed.ncbi.nlm.nih.gov/35895141/
Brandalise F, Cesaroni V, Gregori A, Repetti M, Romano C, Orru G, . . . Rossi P. Dietary Supplementation of Hericium erinaceus Increases Mossy Fiber-CA3 Hippocampal Neurotransmission and Recognition Memory in Wild-Type Mice. Evidence-based complementary and alternative medicine : eCAM. 2017;2017:3864340.
Brinton RD. “Investigative Models for Determining Hormone Therapy-Induced Outcomes in Brain: Evidence in Support of a Healthy Cell Bias of Estrogen Action.” Ann N Y Acad Sci. 2005 Jun;1052:57-74.
Bryson S. 3 months of TB006 eased, reversed signs of Alzheimer's disease: Trial. Bionews, Inc. Updated 4/21/2023. Accessed 9/13/2024, https://alzheimersnewstoday.com/news/signs-alzheimers-reversed-eased-after-3-months-tb006/
Bubenik GA and Konturek SJ. “Melatonin and aging: prospects for human treatment.” J Physiol Pharmacol. 62.1 (2011): 13-9.
Bukhbinder AS, Ling Y, Hasan O, et al. Risk of Alzheimer's Disease Following Influenza Vaccination: A Claims-Based Cohort Study Using Propensity Score Matching. J Alzheimers Dis. 2022;88(3):1061-1074. doi:10.3233/jad-220361. https://content.iospress.com:443/download/journal-of-alzheimers-disease/jad220361?id=journal-of-alzheimers-disease%2Fjad220361
Burns JM, et al. “Cardiorespiratory Fitness and Brain Atrophy in Early Alzheimer Disease.” Neurology. 71.3 (2008): 210-6.
Butt MS, et al. “Coffee and Its Consumption: Benefits and Risks.” Crit Rev Food Sci Nutr. 51.4 (2011): 363-73.
Butterworth RF. “Evidence for Forebrain Cholinergic Neuronal Loss in Congenital Ornithine Transcarbamylase Deficiency.” Metab Brain Dis. 15.1 (2000): 83-91.
Cabrera O, Dougherty J, Singh S, Swiney BS, Farber NB, Noguchi KK. Lithium protects against glucocorticoid induced neural progenitor cell apoptosis in the developing cerebellum. Brain research.Jan 30 2014;1545:54-63.
Cai Z. Monoamine oxidase inhibitors: promising therapeutic agents for Alzheimer's disease (Review). Molecular medicine reports. May 2014;9(5):1533-1541.
Cai Z, et al. “Mammalian Target of Rapamycin: A Valid Therapeutic Target through the Autophagy Pathway for Alzheimer’s disease?” J Neurosci Res. 90.6 (2012): 1105-18.
Cairns DM, Itzhaki RF, Kaplan DL. Potential Involvement of Varicella Zoster Virus in Alzheimer's Disease via Reactivation of Quiescent Herpes Simplex Virus Type 1. J Alzheimers Dis. 2022;88(3):1189-1200. doi:10.3233/jad-220287. https://content.iospress.com/articles/journal-of-alzheimers-disease/jad220287
Canto C, Houtkooper RH, Pirinen E, et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab.Jun 6 2012;15(6):838-847.
Cao C, et al. “Caffeine Synergizes with Another Coffee Component to Increase Plasma GCSF: Linkage to Cognitive Benefits in Alzheimer’s Mice.” J Alzheimers Dis. 25.2 (2011): 323-35.
Cardinali DP, Furio AM, Brusco LI. “The use of chronobiotics in the resynchronization of the sleep/wake cycle. Therapeutical application in the early phases of Alzheimer’s disease.” Recent Pat Endocr Metab Immune Drug Discov. 5.2 (2011): 80-90.
Carroll JC and Rosario ER. “The Potential Use of Hormone-Based Therapeutics for the Treatment of Alzheimer’s Disease.” Curr Alzheimer Res. 2012 Jan;9(1):18-34.
Casadesus G, Shukitt-Hale B, Stellwagen HM, et al. Nutr Neurosci. 7.5-6 (2004): 309-16.
Caselli RJ, Reiman EM. “Characterizing the Preclinical Stages of Alzheimer’s Disease and the Prospect of Presymptomatic Intervention.” J Alzheimers Dis. (2012) [Epub ahead of print]
Castner SA, Gupta S, Wang D, et al. Longevity factor klotho enhances cognition in aged nonhuman primates. Nat Aging. Aug 2023;3(8):931-937. doi:10.1038/s43587-023-00441-x. https://pubmed.ncbi.nlm.nih.gov/37400721/
Chan A, Paskavitz J, Remington R, Rasmussen S, Shea TB. Efficacy of a vitamin/nutriceutical formulation for early-stage Alzheimer's disease: a 1-year, open-label pilot study with an 16-month caregiver extension. Am J Alzheimers Dis Other Demen. Dec-2009 Jan 2008;23(6):571-85. doi:10.1177/1533317508325093. https://pubmed.ncbi.nlm.nih.gov/19047474/
Chen HK, Ji ZS, Dodson SE, et al. “Apolipoprotein E4 Domain Interaction Mediates Detrimental Effects on Mitochondria and Is a Potential Therapeutic Target for Alzheimer Disease.” J Biol Chem. 2011 Feb 18;286(7):5215-21.
Cheng F, et al. “Suppression of Amyloid β A11 Antibody Immunoreactivity by Vitamin C: Possible Role Of Heparan Sulfate Oligosaccharides Derived From Glypican-1 By Ascorbate-induced, Nitric Oxide (NO)-catalyzed Degradation.” J Biol Chem, 286.31 (2011): 27559-72.
Cheng Y, et al. “Beneficial Effects of Melatonin in Experimental Models of Alzheimer Disease.” Acta Pharmacol Sin. 27.2 (2006): 129-39.
Chinnici CM, Yao Y, Pratico D. The 5-lipoxygenase enzymatic pathway in the mouse brain: young versus old. Neurobiology of aging. Sep 2007;28(9):1457-1462.
Chi S, Yu JT, Tan MS, Tan L. Depression in Alzheimer's disease: epidemiology, mechanisms, and management. Journal of Alzheimer's disease : JAD. 2014;42(3):739-755.
Chi Y, Sauve AA. Nicotinamide riboside, a trace nutrient in foods, is a vitamin B3 with effects on energy metabolism and neuroprotection. Current opinion in clinical nutrition and metabolic care.Nov 2013;16(6):657-661.
Chiu CH, Chyau CC, Chen CC, Lee LY, Chen WP, Liu JL, . . . Mong MC. Erinacine A-Enriched Hericium erinaceus Mycelium Produces Antidepressant-Like Effects through Modulating BDNF/PI3K/Akt/GSK-3beta Signaling in Mice. International journal of molecular sciences. Jan 24 2018;19(2).
Choi CH, McBride SM, Schoenfeld BP, et al. Age-dependent cognitive impairment in a Drosophila fragile X model and its pharmacological rescue. Biogerontology.Jun 2010;11(3):347-362.
Choudhary MI, et al. “Cholinesterase Inhibiting Withanolides from Withania somnifera.” Chem Pharm Bull Tokyo. 52.11 (2004): 1358-61.
Chowanadisai W, et al. “Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1alpha expression.” J Biol Chem. 285.1 (2010): 142-152.
Christensen LP. “Ginsenosides chemistry, biosynthesis, analysis, and potential health effects.” Adv Food Nutr Res. 55 (2009): 1-99.
Chu J, Li JG, Pratico D. Zileuton improves memory deficits, amyloid and tau pathology in a mouse model of Alzheimer's disease with plaques and tangles. PloS one. 2013;8(8):e70991.
Chu J, Pratico D. The 5-Lipoxygenase as modulator of Alzheimer's gamma-secretase and therapeutic target. Brain research bulletin. Sep 2016;126(Pt 2):207-212.
Chu J, Pratico D. Pharmacologic blockade of 5-lipoxygenase improves the amyloidotic phenotype of an Alzheimer's disease transgenic mouse model involvement of gamma-secretase. The American journal of pathology. Apr 2011;178(4):1762-1769.
Ciabattoni G, et al. “Determinants of Platelet Activation in Alzheimer’s Disease.” Neurobiol Aging. 28.3 (2007): 336-72. Epub ahead of print January 24, 2006.
Clinicaltrials.gov. NCT01617577. Efficacy and Safety of Filgrastim in Alzheimer's Disease (FFAD) Available at: http://clinicaltrial.gov/ct2/show/NCT01617577?term=Granulocyte+Colony-stimulating+Factor&rank=15 Accessed 7/25/2012.
Cole GM, et al. “NSAID and Antioxidant Prevention of Alzheimer’s Disease: Lessons from in Vitro and Animal Models.” Ann N Y Acad Sci. 1035 (2004): 68-84.
Colomina MT and Peris-Sampedro F. Aluminum and Alzheimer's Disease. Adv Neurobiol. 2017;18: 183-197.
Corrêa HdL, Raab ATO, Araújo TM, et al. A systematic review and meta-analysis demonstrating Klotho as an emerging exerkine. Scientific Reports. 2022;12(1):17587. doi:10.1038/s41598-022-22123-1. https://pubmed.ncbi.nlm.nih.gov/36266389/
Corsonello A, et al. “Serum Magnesium Levels and Cognitive Impairment in Hospitalized Hypertensive Patients.” Magnes Res. 14.4 (2001): 273-82.
Cotman CW, et al. “Exercise Builds Brain Health: Key Roles of Growth Factor Cascades and Inflammation.” Trends Neurosci. 30.9 (2007): 464-72.
Crack PJ, et al. Lack of Glutathione Peroxidase-1 Exacerbates Abeta-Mediated Neurotoxicity in Cortical Neurons.” J Neural Transm 113.5 (2006): 645-57. Epub ahead of print October 21, 2005.
Creeley CE, et al. “Donepezil Markedly Potentiates Memantine Neurotoxicity in the Adult Rat Brain.” Neurobiol Aging. 29.2 (2008): 153-67.
Crespo-Biel N, Theunis C, and Van Leuven F. Protein tau: prime cause of synaptic and neuronal degeneration in Alzheimer's disease. Int J Alzheimers Dis. 2012;2012:251426.
Culpan d, Kehoe PG, Love S. “Tumor necrosis factor-α (TNF-α) and miRNA expression in frontal and temporal neocortex in Alzheimer’s disease and the effect of TNFα on miRNA expression in vitro.” Int J Mol Epidemiol Genet. 2.2 (2011): 156-62.
Cummings J, Osse AML, Cammann D, Powell J, Chen J. Anti-Amyloid Monoclonal Antibodies for the Treatment of Alzheimer's Disease. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. Jan 2024;38(1):5-22. doi:10.1007/s40259-023-00633-2. https://pubmed.ncbi.nlm.nih.gov/37955845/
Danysz W, Parsons CG. “Alzheimer′s disease, β-amyloid, glutamate, NMDA receptors and memantine – searching for the connections.” Br J Pharmacol. 2012 May 30. doi: 10.1111/j.1476-5381.2012.02057.x. [Epub ahead of print]
Daviglus ML, et al. “Risk Factors and Preventive Interventions for Alzheimer’s disease: State of the Science.” Arch Neurol. 68.9 (2011): 1185-90.
de Jong DLK, de Heus RAA, Rijpma A, et al. Effects of Nilvadipine on Cerebral Blood Flow in Patients With Alzheimer Disease. Hypertension. 2019 Aug;74(2):413-420.
de la Monte SM. Insulin Resistance and Neurodegeneration: Progress Towards the Development of New Therapeutics for Alzheimer's Disease. Drugs. 2017;77(1): 47-65.
de la Monte SM, et al. The 20-Year Voyage Aboard the Journal of Alzheimer's Disease: Docking at 'Type 3 Diabetes', Environmental/Exposure Factors, Pathogenic Mechanisms, and Potential Treatments. J Alzheimers Dis. 2018;62(3): 1381-1390.
Deleglise B, Lassus B, Soubeyre V, et al. Synapto-protective drugs evaluation in reconstructed neuronal network. PloS one.2013;8(8):e71103.
Delumeau JC, Bentue-Ferrer D, Gandon JM, Amrein R, Belliard S, Allain H. Monoamine oxidase inhibitors, cognitive functions and neurodegenerative diseases. Journal of neural transmission. Supplementum.1994;41:259-266.
Demarin V, et al. “Mediterranean Diet in Healthy Lifestyle and Prevention of Stroke.” Acta Clin Croat. 50.1 (2011): 67-77.
Demarin V, Podobnik SS, Storga-Tomic D, Kay G. Treatment of Alzheimer's disease with stabilized oral nicotinamide adenine dinucleotide: a randomized, double-blind study. Drugs under experimental and clinical research.2004;30(1):27-33.
De-Paula VJ, Gattaz WF, Forlenza OV. Long-term lithium treatment increases intracellular and extracellular brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons at subtherapeutic concentrations. Bipolar disorders.Nov 24 2016.
De-Paula VJ, Kerr DS, Scola G, Gattaz WF, Forlenza OV. Lithium Distinctly Modulates the Secretion of Pro- and Anti- Inflammatory Interleukins in Co-Cultures of Neurons and Glial Cells at Therapeutic and Sub-Therapeutic Concentrations. Current Alzheimer research. 2016;13(8):848-852.
Dézsi L, et al. “Neuroprotective Effects of Vinpocetine in Vivo and in Vitro: Apovincaminic Acid Derivatives as Potential Therapeutic Tools in Ischemic Stroke” [in Hungarian]. Acta Pharm Hung. 72.2 (2002): 84-91.
Dhanasekaran M, et al. “The Emerging Role of Coenzyme Q-10 in Aging, Neurodegeneration, Cardiovascular Disease, Cancer and Diabetes Mellitus.” Curr Neurovasc Res. 2.5 (2005): 447-59.
Dhitavat S, et al. “Folate, Vitamin E, and Acetyl-L-Carnitine Provide Synergistic Protection against Oxidative Stress Resulting from Exposure of Human Neuroblastoma Cells to Amyloid-Beta.” Brain Res. 1061.2 (2005): 114-7.
Diamond BJ, et al. “Ginkgo biloba Extract: Mechanisms and Clinical Indications.” Arch Phys Med Rehab. 81.5 (2000): 668-78.
Dimpfel W, Storni C, Verbruggen M. Ingested oat herb extract (Avena sativa) changes EEG spectral frequencies in healthy subjects. Journal of alternative and complementary medicine.May 2011;17(5):427-434.
Di Meco A, Lauretti E, Vagnozzi AN, Pratico D. Zileuton restores memory impairments and reverses amyloid and tau pathology in aged Alzheimer's disease mice. Neurobiology of aging. Nov 2014;35(11):2458-2464.
Dominy S, Lynch C, Ermini F et al. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. 2019;5(1):eaau3333.
Dong-gyu J, et al. “Evidence That γ-Secretase Mediates Oxidative-Stress Induced β-Secretase Expression in Alzheimer’s disease.” Neurobiol Aging. 2010 Jun;31(6):917-25.
Douraghi-Zadeh D, Matharu B, Razvi A, Austen B. The protective effects of the nutraceutical, colostrinin, against Alzheimer's disease, is mediated via prevention of apoptosis in human neurones induced by aggregated beta-amyloid. The journal of nutrition, health & aging.Jun
2009;13(6):522-527.
Dubal DB, Zhu L, Sanchez PE, et al. Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice. The Journal of Neuroscience. 2015;35(6):2358. doi:10.1523/JNEUROSCI.5791-12.2015. https://pubmed.ncbi.nlm.nih.gov/25673831/
Dyer O. Aduhelm: Biogen abandons Alzheimer's drug after controversial approval left it unfunded by Medicare. BMJ. Feb 2 2024;384:q281. doi:10.1136/bmj.q281. https://pubmed.ncbi.nlm.nih.gov/38307520/
Ebell MH, Barry HC, Baduni K, Grasso G. Clinically Important Benefits and Harms of Monoclonal Antibodies Targeting Amyloid for the Treatment of Alzheimer Disease: A Systematic Review and Meta-Analysis. Ann Fam Med. Jan-Feb 2024;22(1):50-62. doi:10.1370/afm.3050. https://pubmed.ncbi.nlm.nih.gov/38253509/
Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, et al. Alzheimer's Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection. Neuron. Jul 11 2018;99(1):56-63.e3. doi:10.1016/j.neuron.2018.06.030.
Ejaz P, Bhojani K, Joshi VR. NSAIDs and kidney. J Assoc Physicians India. 2004 Aug;52:632-40.
Engel T, Goni-Oliver P, Gomez de Barreda E, Lucas JJ, Hernandez F, Avila J. Lithium, a potential protective drug in Alzheimer's disease. Neuro-degenerative diseases.2008;5(3-4):247-249.
Engelborghs S, et al. “Correlations between Cognitive, Behavioural and Psychological Findings and Levels of Vitamin B12 and Folate in Patients with Dementia.” Int J Geriatr Psychiatry. 19.4 (2004): 365-70.
Engelborghs S, Le Bastard N. “The impact of cerebrospinal fluid biomarkers on the diagnosis of Alzheimer’s disease.” Mol Diagn Ther. 16.3 (2012): 135-41.
Epis R, et al. “Modulatory Effect of Acetyl-L-Carnitine on Amyloid Precursor Protein Metabolism in Hippocampal Neurons.” Eur J Pharmocol. 597.1-3 (2008): 51-53.
Eyles DW, et al. “Distribution of the Vitamin D Receptor and 1α-hydroxylase in Human Brain.” J Chem Neuroanat. 29.1 (2005): 21-30.
Eyting M, Xie M, Heß S, Heß S, Geldsetzer P. Causal evidence that herpes zoster vaccination prevents a proportion of dementia cases. medRxiv. May 25 2023;doi:10.1101/2023.05.23.23290253.
Facecchia K, et al. “Oxidative Toxicity in Neurodegenerative Diseases: Role of Mitochondrial Dysfunction and Therapeutic Strategies.” J Toxicol. 2011 (2011): 683728. Epub ahead of print July 14, 2011.
Farr SA, et al. “DHEAS Improves Learning and Memory in Aged SAMP8 Mice but Not in Diabetic Mice.” Life Sci. 75.2 (2004): 2775-85.
Feart C, Letenneur L, Helmer C, et al. Plasma Carotenoids Are Inversely Associated With Dementia Risk in an Elderly French Cohort. The journals of gerontology Series A, Biological sciences and medical sciences. 2016;71(5):683-688.
Fenton L, Isenberg AL, Aslanyan V, et al. Variability in objective sleep is associated with Alzheimer's pathology and cognition. Brain Commun. 2023;5(2): fcad031. https://pubmed.ncbi.nlm.nih.gov/36895954/
Ferensztajn-Rochowiak E and Rybakowski JK. The effect of lithium on hematopoietic, mesenchymal and neural stem cells. Pharmacol Rep. 2016;68(2): 224-230.
Finali G, Piccirilli M, Oliani C, Piccinin GL. L-deprenyl therapy improves verbal memory in amnesic Alzheimer patients. Clinical neuropharmacology.Dec 1991;14(6):523-536.
Fleisher AS, et al. “Phase 2 Safety Trial Targeting Amyloid Beta Production with a Gamma-Secretase Inhibitor in Alzheimer Disease.” Arch Neurol. 65.8 (2008): 1031-8.
Foley KE, Wilcock DM. Three major effects of APOE(ε4) on Aβ immunotherapy induced ARIA. Front Aging Neurosci. 2024;16:1412006. doi:10.3389/fnagi.2024.1412006. https://pubmed.ncbi.nlm.nih.gov/38756535/
Fonte V, Dostal V, Roberts CM et al. A glycine zipper motif mediates the formation of toxic β-amyloid oligomers in vitro and in vivo. Mol Neurodegener. 2011 Aug 23;6(1):61.
Food and Drug Administration (FDA). Drugs page. Drugs to be Discontinued. Available at: http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050794.htm. Last updated 5/28/2013. Accessed 5/28/2013.
Forette F, et al. “Prevention of Dementia in Randomised Double-Blind Placebo-Controlled Systolic Hypertension in Europe (Syst-Eur) Trial.” Lancet. 352.9137 (1998): 1347-51.
Forlenza OV, De-Paula VJ, Diniz BS. Neuroprotective effects of lithium: implications for the treatment of Alzheimer's disease and related neurodegenerative disorders. ACS chemical neuroscience.Jun 18 2014;5(6):443-450.
Forlenza OV, et al. “Disease-Modifying Properties of Long-Term Lithium Treatment for Amnestic Mild Cognitive Impairment: Randomised Controlled Trial.” Br J Psychiatry. 198 (2011): 351-6.
Forman HJ, et al. “Glutathione: Overview of its Protective Roles, Measurement, and Biosynthesis.” Mol Aspects Med. 30.1-2 (2009): 1-12.
Galbusera C, et al. “Increased Susceptibility to Plasma Lipid Peroxidation in Alzheimer Disease Patients.” Curr Alzheimer Res. 1.2 (2004): 103-9.
Galpern WR, et al. “Coenzyme Q Treatment of Neurodegenerative Diseases of Aging.” Mitochondrion. 7 Supp (2007): S146-53.
Gao J, Wang WY, Mao YW, et al. A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature.Aug 26 2010;466(7310):1105-1109.
Garcia-Revilla J, Boza-Serrano A, Espinosa-Oliva AM, et al. Galectin-3, a rising star in modulating microglia activation under conditions of neurodegeneration. Cell Death Dis. Jul 20 2022;13(7):628. doi:10.1038/s41419-022-05058-3. https://pubmed.ncbi.nlm.nih.gov/35859075/
Gauthier S, et al. “Can We Do Better in Developing New Drugs for Alzheimer’s Disease?” Alzheimers Dement. 5.6 (2009): 489-91.
Geda Y, et al. “Caloric Intake, Aging, and Mild Cognitive Impairment: A Population-Based Study.” Presented at the 64th Annual Meeting of the American Academy of Neurology. New Orleans. April 21-28, 2012.
Giannopoulos PF, Chu J, Joshi YB, Sperow M, Li JG, Kirby LG, Pratico D. Gene knockout of 5-lipoxygenase rescues synaptic dysfunction and improves memory in the triple-transgenic model of Alzheimer's disease. Molecular psychiatry. Apr 2014;19(4):511-518.
Giannopoulos PF, Chiu J, Pratico D. Antileukotriene therapy by reducing tau phosphorylation improves synaptic integrity and cognition of P301S transgenic mice. Aging cell. Jun 2018a;17(3):e12759.
Giannopoulos PF, Chiu J, Pratico D. Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase Pathway. Molecular neurobiology. Jun 7 2018b.
Gibson GE, et al. Benfotiamine and Cognitive Decline in Alzheimer's Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial. J Alzheimers Dis. 2020;78(3): 989-1010.
Gehin A, et al. “Glyphosate-induced Antioxidant Imbalance in HaCaT: The Protective Effect of Vitamins C and E.” Environ Toxicol Pharmocol. 22.1 (2006): 27-34.
Gitlin M. Lithium side effects and toxicity: prevalence and management strategies. International journal of bipolar disorders.Dec 2016;4(1):27.
Godhia ML, Patel N. Colostrum–its Composition, Benefits as a Nutraceutical–A Review. Current Research in Nutrition and Food Science Journal.2013;1(1):37-47.
Gomez-Pinilla F, et al. “Brain-Derived Neurotrophic Factor Functions as a Metabotrophin to Mediate the Effects of Exercise on Cognition.” Eur J Neurosci. 28.11 (2008): 2278-87.
Gong B, Pan Y, Vempati P, et al. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-gamma coactivator 1alpha regulated beta-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models. Neurobiol Aging.Jun
2013;34(6):1581-1588.
Grimmig B, Kim SH, Nash K, Bickford PC, Douglas Shytle R. Neuroprotective mechanisms of astaxanthin: a potential therapeutic role in preserving cognitive function in age and neurodegeneration. GeroScience. Feb 2017;39(1):19-32.
Grundman M. “Vitamin E and Alzheimer Disease: The Basis for Additional Clinical Trials.” Am J Clin Nutr. 71.2 (2000): 630S-6S.
Grzybowski A, Barboni P. OCT and Imaging in Central Nervous System Diseases: The Eye as a Window to the Brain. Springer Nature; 2020.
Gu X, Qi L, Qi Q, Zhou J, Chen S, Wang L. Monoclonal antibody therapy for Alzheimer's disease focusing on intracerebral targets. Bioscience trends. Mar 19 2024;18(1):49-65. doi:10.5582/bst.2023.01288. https://pubmed.ncbi.nlm.nih.gov/38382942/
Gu Y, et al. “Dietary Patterns in Alzheimer’s Disease and Cognitive Aging.” Curr Alzheimer Res. 8.5 (2011): 510-9.
Guedes AC, Amaro HM, Malcata FX. Microalgae as sources of carotenoids. Marine drugs. 2011;9(4):625-644.
Gutzmann H, and Hadler D. Sustained Efficacy and Safety of Idebenone in the Treatment of Alzheimer's Disease: Update on a 2-Year Double-Blind Multicentre Study. [In eng] J Neural Transm Suppl. 1998 54(301-10.
Gutzmann H, Kuhl KP, Hadler D, et al. Safety and Efficacy of Idebenone Versus Tacrine in Patients with Alzheimer's Disease: Results of a Randomized, Double-Blind, Parallel-Group Multicenter Study. [In eng] Pharmacopsychiatry. 2002 Jan; 35(1): 12-8.
Hager K, et al. “Alpha-Lipoic Acid as a New Treatment Option for Alzheimer [corrected] Type Dementia.” Arch Gerontol Geriatr. 32.3 (2001): 275-82.
Hager K, et al. “Alpha-Lipoic Acid as a New Treatment Option for Alzheimer's Disease—A 48 Months Follow-up Analysis.” J Neural Transm Suppl. 72 (2007): 189-93.
Hajjar IM, et al. “Angiotensin Converting Enzyme Inhibitors and Cognitive and Functional Decline in Patients with Alzheimer’s Disease: An Observational Study.” Am J Alzheimers Dis Other Demen. 23.1 (2008): 77-83.
Halmos T and Suba I. [Alzheimer's disease and diabetes - the common pathogenesis]. Neuropsychopharmacol Hung. 2016;18(1): 5-19.
Hampel H, Prvulovic D, Teipel S, et al. The future of Alzheimer's disease: the next 10 years. Prog Neurobiol. 2011 Dec;95(4):718-28.
Han JH, Lee YS, Im JH, et al. Astaxanthin Ameliorates Lipopolysaccharide-Induced Neuroinflammation, Oxidative Stress and Memory Dysfunction through Inactivation of the Signal Transducer and Activator of Transcription 3 Pathway. Mar Drugs. 2019;17(2).
Hansen RA, et al. “Efficacy and Safety of Donepezil, Galantamine, and Rivastigmine for the Treatment of Alzheimer’s Disease: A Systematic Review and Meta-Analysis.” Clin Interv Aging. 3.2 (2008): 211-25.
Haque AM, et al. “Green Tea Catechins Prevent Cognitive Deficits Caused by Abeta1-40 in Rats.” J Nutr Biochem. 19.9 (2008): 619-26.
Harris E. FDA Green-Lights Second Alzheimer Drug, Donanemab. Jama. Aug 20 2024;332(7):524. doi:10.1001/jama.2024.13386. https://pubmed.ncbi.nlm.nih.gov/39058481/
Harrison FE. “A critical review of vitamin C for the prevention of age-related cognitive decline and Alzheimer’s disease.” J Alzheimer’s Dis. 29.4 (2012): 711-26.
Haskell CF, et al. “Effects of a Multi-Vitamin/Mineral Supplement on Cognitive Function and Fatigue During Extended Multi-Tasking.” Hum Psychopharmacol. 25.6 (2010): 448-61.
Hayden K. M., Zandi P. P., Khachaturian A. S., et al. Cache County Investigators (2007). Does NSAID use modify cognitive trajectories in the elderly? The Cache County study. Neurology 69, 275–282.
Hedi H, Norbert G. 5-Lipoxygenase Pathway, Dendritic Cells, and Adaptive Immunity. Journal of biomedicine & biotechnology. 2004;2004(2):99-105.
Hendrix SB, Soininen H, Solomon A, et al. Combined Evidence for a Long-Term, Clinical Slowing Effect of Multinutrient Intervention in Prodromal Alzheimer's Disease: Post-Hoc Analysis of 3-Year Data from the LipiDiDiet Trial. The journal of prevention of Alzheimer's disease. 2023;10(3):464-470. doi:10.14283/jpad.2023.29. https://pubmed.ncbi.nlm.nih.gov/37357286/
Hillen T, et al. “DHEA-S Plasma Levels and Incidence of Alzheimer’s Disease.” Biol Psychiatry. 47.2 (2000): 161-3.
Hinterberger M and Fischer P. “Folate and Alzheimer: when time matters.” J Neural Transm. 2012 May 25. [Epub ahead of print]
Ho L, et al. “Heterogeneity in Red Wine Polyphenolic Contents Differentially Influences Alzheimer’s Disease-Type Neuropathology and Cognitive Deterioration.” J Alzheimers Dis. 16.1 (2009): 59-72.
Holmes C, et al. “Long-Term Effects of Abeta42 Immunisation in Alzheimer’s Disease: Follow-Up of a Randomised, Placebo-Controlled Phase I Trial.” Lancet. 2008 Jul 19;372(9634):216-23.
Holmquist L, et al. “Lipoic Acid as a Novel Treatment for Alzheimer’s disease and Related Dementias.” Pharmacol Thera. 113.1 (2007): 154-164.
Hongo N, Takamura Y, Nishimaru H, et al. Astaxanthin Ameliorated Parvalbumin-Positive Neuron Deficits and Alzheimer's Disease-Related Pathological Progression in the Hippocampus of App(NL-G-F/NL-G-F) Mice. Frontiers in pharmacology. 2020;11:307.
Honjo K, van Reekum R, Verhoeff NP. Alzheimer's disease and infection: do infectious agents contribute to progression of Alzheimer's disease? Alzheimers Dement. 2009 Jul;5(4):348-60.
Houck AL, Hernandez F, Avila J. A Simple Model to Study Tau Pathology. Journal of experimental neuroscience.2016;10:31-38.
Houtkooper RH, Canto C, Wanders RJ, Auwerx J. The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr Rev. Apr 2010;31(2):194-223.
Huat TJ, et al. Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation. J Mol Biol. 2019;431(9): 1843-1868.
Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol.Aug 2014;24(8):464-471.
Israel E, Cohn J, Dube L, Drazen JM. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. A randomized controlled trial. Zileuton Clinical Trial Group. Jama. Mar 27 1996;275(12):931-936.
Ito N, Saito H, Seki S, Ueda F, Asada T. Effects of Composite Supplement Containing Astaxanthin and Sesamin on Cognitive Functions in People with Mild Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled Trial. J Alzheimers Dis. 2018;62(4):1767-1775.
Ito S, et al. “1-alpha,25-Dihydroxyvitamin D3 Enhances Cerebral Clearance of Human Amyloid-Β Peptide(1-40) from Mouse Brain across the Blood-Brain Barrier.” Fluids Barriers CNS. 8 (2011): 20.
Ittner LM and Götz J. Amyloid-β and tau--a toxic pas de deux in Alzheimer's disease. Nat Rev Neurosci. 2011 Feb;12(2):65-72.
Jaiswal R, et al. “Profile and characterization of the chlorogenic acids in green Robusta coffee beans by LC-MS(n): identification of seven new classes of compounds.” J Agric Food Chem. 58.15 (2010): 8722-37.
Janssen IM, et al. “Ginkgo biloba in Alzheimer’s Disease: A Systematic Review.” Wien Med Wochenschr. 160.21-22 (2010): 539-46.
Janusz M, Woszczyna M, Lisowski M, Kubis A, Macala J, Gotszalk T, Lisowski J. Ovine colostrum nanopeptide affects amyloid beta aggregation. FEBS letters.Jan 05 2009;583(1):190-196.
Janusz M, Zablocka A. Colostral proline-rich polypeptides--immunoregulatory properties and prospects of therapeutic use in Alzheimer's disease. Current Alzheimer research.Jun 2010;7(4):323-333.
Janusz M, Zablocka A. Colostrinin: a proline-rich polypeptide complex of potential therapeutic interest. Cellular and molecular biology (Noisy-le-Grand, France).Nov 03 2013;59(1):4-11.
Ji X, Peng D, Zhang Y, Zhang J, Wang Y, Gao Y, . . . Tang P. Astaxanthin improves cognitive performance in mice following mild traumatic brain injury. Brain research. Mar 15 2017;1659:88-95.
Jiang H, et al. “Granulocyte Colony-Stimulating Factor Attenuates Chronic Neuroinflammation in the Brain of Amyloid Precursor Protein Transgenic Mice: An Alzheimer’s Disease Mouse Model.” J Int Med Res. 38.4 (2010): 1305-12.
Joshi YB, Pratico D. The 5-lipoxygenase pathway: oxidative and inflammatory contributions to the Alzheimer's disease phenotype. Frontiers in cellular neuroscience. 2014;8:436.
Jossan SS, Gillberg PG, Gottfries CG, Karlsson I, Oreland L. Monoamine oxidase B in brains from patients with Alzheimer's disease: a biochemical and autoradiographical study. Neuroscience.1991;45(1):1-12.
Jóźwiak S, et al. “Dietary Treatment of Epilepsy: Rebirth of an Ancient Treatment.” Neurol Neurochir Pol. 45.4 (2011): 370-8.
Kado DM, et al. “Homocysteine versus the Vitamins Folate, B6, and B12 as Predictors of Cognitive Function and Decline in Older High-Functioning Adults: MacArthur Studies of Successful Aging.” Am J Med. 118.2 (2005): 161-7.
Kalaria RN, Akinyemi R, and Ihara M. Does Vascular Pathology Contribute to Alzheimer Changes? [In Eng] J Neurol Sci. 2012 Aug 9;
Kamer AR, et al. Periodontal dysbiosis associates with reduced CSF Aβ42 in cognitively normal elderly. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. 2021;13(1): e12172.
Kanbay M, Copur S, Ozbek L, et al. Klotho: a potential therapeutic target in aging and neurodegeneration beyond chronic kidney disease-a comprehensive review from the ERA CKD-MBD working group. Clin Kidney J. Jan 2024;17(1):sfad276. doi:10.1093/ckj/sfad276. https://pubmed.ncbi.nlm.nih.gov/38213484/
Kariv-Inbal Z, Yacobson S, Berkecz R, et al. The isoform-specific pathological effects of apoE4 in vivo are prevented by a fish oil (DHA) diet and are modified by cholesterol. J Alzheimers Dis. 2012;28(3):667-83.
Karl TB, et al. The therapeutic potential of the phytocannabinoid cannabidiol for Alzheimer's disease. Behav Pharmacol. 2017;28(2 and 3-Spec Issue): 142-160.
Kasper DL, et al., eds. Harrison’s Principles of Internal Medicine, 16th ed. McGraw-Hill, New York, 2004.
Katagiri M, Satoh A, Tsuji S, Shirasawa T. Effects of astaxanthin-rich Haematococcus pluvialis extract on cognitive function: a randomised, double-blind, placebo-controlled study. Journal of clinical biochemistry and nutrition. Sep 2012;51(2):102-107.
Kato-Kataoka A, et al. “Soybean-derived Phosphatidylserine Improves Memory Functions of the Elderly Japanese Subjects with Memory Complaints.” J Clin Biochem Nutr. 47.3 (2010) 246-55.
Kellar D and Craft S. Brain insulin resistance in Alzheimer's disease and related disorders: mechanisms and therapeutic approaches. Lancet Neurol. 2020;19(9): 758-766.
Kelly D, Coen RF, Akuffo KO, et al. Cognitive Function and Its Relationship with Macular Pigment Optical Density and Serum Concentrations of its Constituent Carotenoids. J Alzheimers Dis. 2015;48(1):261-277.
Kelley BJ, Petersen RC. Alzheimer's disease and mild cognitive impairment. Neurologic clinics. Aug 2007;25(3):577-609, v.
Kennedy DO, et al. “Acute Cognitive Effects of Standardised Ginkgo Biloba Extract Complexed with Phosphatidylserine.” Hum Psychopharmacol. 22.4 (2007): 199-210.
Kennedy DO, et al. “Dose Dependent Changes in Cognitive Performance and Mood Following Acute Administration of Ginseng to Healthy Young Volunteers.” Nutr Neurosci. 4.4 (2001): 295-310.
Kennedy DO, Jackson PA, Forster J, Khan J, Grothe T, Perrinjaquet-Moccetti T, Haskell-Ramsay CF. Acute effects of a wild green-oat (Avena sativa) extract on cognitive function in middle-aged adults: A double-blind, placebo-controlled, within-subjects trial. Nutritional neuroscience.Nov 30 2015.
Khan MA, Tania M, Liu R, Rahman MM. Hericium erinaceus: an edible mushroom with medicinal values. Journal of complementary & integrative medicine. May 24 2013;10.
Khodadadi HL, et al. Cannabidiol Ameliorates Cognitive Function via Regulation of IL-33 and TREM2 Upregulation in a Murine Model of Alzheimer's Disease. J Alzheimers Dis. 2021;80(3): 973-977.
Kidd PM. “Neurodegeneration from Mitochondrial Insufficiency: Nutrients, Stem Cells, Growth Factors, and Prospects for Brain Rebuilding Using Integrative Management.” Altern Med Rev. 10.4 (2005): 268-93.
Kim D, et al. “SIRT1 Deacetylase Protects against Neurodegeneration in Models for Alzheimer’s Disease and Amyotrophic Lateral Sclerosis.” EMBO J. 26.13 (2007): 3169-79.
Kim J, et al. Holtzman. Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Abeta amyloidosis. J Exp Med. 2012;209(12): 2149-2156.
Kim J, et al. “The Inhibitory Effect of Pyrroloquinoline Quinone on the Amyloid Formation and Cytotoxicity of Truncated Alpha-Synuclein.” Mol Neurodegener. 5 (2010): 20.
Kim TI, et al. “L-Theanine, an Amino Acid in Green Tea, Attenuates Beta-Amyloid-Induced Cognitive Dysfunction and Neurotoxicity: Reduction in Oxidative Damage and Inactivation of ERK/p38 Kinase and NF-kappaB Pathways.” Free Radic Biol Med. 47.11 (2009): 1601-10.
King MK, et al. Glycogen synthase kinase-3 inhibitors: Rescuers of cognitive impairments. Pharmacol Ther. 2014;141(1): 1-12.
Kivipelto M, Mangialasche F, Snyder HM, et al. World-Wide FINGERS Network: A global approach to risk reduction and prevention of dementia. Alzheimers Dement. Jul 2020;16(7):1078-1094. doi:10.1002/alz.12123. https://pubmed.ncbi.nlm.nih.gov/32627328/
Knopman DS. Alzheimer’s Disease and Other Dementias. In: Goldman L, Schafer AI. Goldman’s Cecil Medicine. 24th ed. Philadelphia, PA:Elsevier;2012. Available at: http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-1604-7..00409-7&isbn=978-1-4377-1604-7&uniqId=349213967-58#4-u1.0-B978-1-4377-1604-7..00409-7--s0010. Accessed August 3, 2012.
Kuboyama T, et al. “Neuritic Regeneration and Synaptic Reconstruction Induced by Withanolide A.” Br J Pharmacol. 144.7 (2005): 961-71.
Kundu P, Zimmerman B, Quinn JF, et al. Serum Levels of α-Klotho Are Correlated with Cerebrospinal Fluid Levels and Predict Measures of Cognitive Function. J Alzheimers Dis. 2022;86(3):1471-1481. doi:10.3233/jad-215719. https://pubmed.ncbi.nlm.nih.gov/35213382/
Kuriyama N, Ozaki E, Mizuno T, et al. Association between α-Klotho and Deep White Matter Lesions in the Brain: A Pilot Case Control Study Using Brain MRI. Journal of Alzheimer's Disease. 2018;61:145-155. doi:10.3233/JAD-170466. https://pubmed.ncbi.nlm.nih.gov/29154273/
Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390(6655):45-51. doi:10.1038/36285. https://pubmed.ncbi.nlm.nih.gov/9363890/
Kurosu H, Yamamoto M, Clark JD, et al. Suppression of aging in mice by the hormone Klotho. Science. Sep 16 2005;309(5742):1829-33. doi:10.1126/science.1112766. https://pubmed.ncbi.nlm.nih.gov/16123266/
Kwon SH, et al. “Neuroprotective Effects of Chlorogenic Acid on Scopolamine-Induced Amnesia via Anti-Acetylcholinesterase and Anti-Oxidative Activities in Mice.” Eur J Pharmacol. 649.1-3 (2010): 210-7.
Laake K, Oeksengaard AR. D-cycloserine for Alzheimer's disease. The Cochrane database of systematic reviews. 2002(2):Cd003153.
Ladiwala ARA, et al. “Resveratrol Selectively Remodels Soluble Oligomers and Fibrils of Amyloid Beta into Off-Pathway Conformers.” J Biol Chem. 285 (2010): 24228-37.
Lakey-Beitia J, Kumar DJ, Hegde ML, Rao KS. Carotenoids as Novel Therapeutic Molecules Against Neurodegenerative Disorders: Chemistry and Molecular Docking Analysis. International journal of molecular sciences. 2019;20(22).
Landmark K. “Could Intake of Vitamins C and E Inhibit Development of Alzheimer Dementia?” [in Norwegian]. Tidsskr Nor Laegeforen. 126.2 (2006): 159-61.
Laske C, et al. “Decreased Plasma Levels of Granulocyte-Colony Stimulating Factor (G-CSF) in Patients with Early Alzheimer’s Disease.” J Alzheimers Dis. 17.1 (2009): 115-23.
Lau FC, et al. “The Beneficial Effects of Fruit Polyphenols on Brain Aging.” Neurobiol Aging. 26.1 (2005): 128-32.
Lee EH, Kim GH, Park HK, et al. Effects of the multidomain intervention with nutritional supplements on cognition and gut microbiome in early symptomatic Alzheimer's disease: a randomized controlled trial. Front Aging Neurosci. 2023;15:1266955. doi:10.3389/fnagi.2023.1266955. https://pubmed.ncbi.nlm.nih.gov/38020771/
Lee HJ, et al. Diabetes and Alzheimer's Disease: Mechanisms and Nutritional Aspects. Clinical nutrition research. 2018;7(4): 229-240.
Lee ST, et al. “Panax ginseng Enhances Cognitive Performance in Alzheimer Disease.” Alzheimer Dis Assoc Disord. 22.3 (2008): 222-6.
Lee YM, Han SI, Song BC, Yeum KJ. Bioactives in Commonly Consumed Cereal Grains: Implications for Oxidative Stress and Inflammation. Journal of medicinal food.Nov 2015;18(11):1179-1186.
Lehrer S, Rheinstein PH. Herpes Zoster Vaccination Reduces Risk of Dementia. In Vivo. Nov-Dec 2021;35(6):3271-3275. doi:10.21873/invivo.12622. https://iv.iiarjournals.org/content/invivo/35/6/3271.full.pdf
Lehrer S, Rheinstein PH. Vaccination Reduces Risk of Alzheimer's Disease, Parkinson's Disease and Other Neurodegenerative Disorders. Discovery medicine. Sep-Oct 2022;34(172):97-101.
Leszek J, Inglot AD, Janusz M, Byczkiewicz F, Kiejna A, Georgiades J, Lisowski J. Colostrinin proline-rich polypeptide complex from ovine colostrum--a long-term study of its efficacy in Alzheimer's disease. Medical science monitor: international medical journal of experimental and clinical
research.Oct 2002;8(10):Pi93-96.
Leszek J, Inglot AD, Janusz M, Lisowski J, Krukowska K, Georgiades JA. Colostrinin: a proline-rich polypeptide (PRP) complex isolated from ovine colostrum for treatment of Alzheimer's disease. A double-blind, placebo-controlled study. Archivum immunologiae et therapiae experimentalis.
1999;47(6):377-385.
Leuner K, Müller WE, and Reichert AS. From Mitochondrial Dysfunction to Amyloid Beta Formation: Novel Insights into the Pathogenesis of Alzheimer's Disease. Mol Neurobiol. 2012 Jul 26. [Epub ahead of print]
Li G, et al. “Cerebrospinal Fluid Concentration of Brain-Derived Neurotrophic Factor and Cognitive Function in Non-Demented Subjects.” PLoS One. 4.5 (2009): Epub ahead of print May 1, 2009.
Li H, et al. Overview of cannabidiol (CBD) and its analogues: Structures, biological activities, and neuroprotective mechanisms in epilepsy and Alzheimer's disease. Eur J Med Chem. 2020;192: 112163.
Li MH, et al. “Protective Effects of Oligomers of Grape Seed Polyphenols against Beta-Amyloid-Induced Oxidative Cell Death.” Ann NY Acad Sci. 1030 (2004): 317-29.
Li Q, Barres BA. Microglia and macrophages in brain homeostasis and disease. Nature Reviews Immunology. 2018;18(4):225-242. doi:10.1038/nri.2017.125. https://pubmed.ncbi.nlm.nih.gov/29151590/
Li X, Qi Z, Zhao L, Yu Z. Astaxanthin reduces type 2 diabeticassociated cognitive decline in rats via activation of PI3K/Akt and attenuation of oxidative stress. Molecular medicine reports. Jan 2016;13(1):973-979.
Lima VC, Rosen RB, Farah M. Macular pigment in retinal health and disease. Int J Retina Vitreous. 2016;2:19.
Linghui D, Simin Y, Zilong Z, Yuxiao L, Shi Q, Birong D. The relationship between serum klotho and cognitive performance in a nationally representative sample of US adults. Front Aging Neurosci. 2023;15:1053390. doi:10.3389/fnagi.2023.1053390. https://pubmed.ncbi.nlm.nih.gov/36819720/
Liu S, et al. “Enhanced Rat Sciatic Nerve Regeneration through Silicon Tubes Filled with Pyrroloquinoline Quinone.” Microsurgery. 25.4 (2005): 329-37.
Liu Y, Wang W, Li Y, Xiao Y, Cheng J, Jia J. The 5-Lipoxygenase Inhibitor Zileuton Confers Neuroprotection against Glutamate Oxidative Damage by Inhibiting Ferroptosis. Biological & pharmaceutical bulletin. 2015;38(8):1234-1239.
Lo D and Grossberg GT. Use of memantine for the treatment of dementia. Expert Rev Neurother. 2011 Oct;11(10):1359-70.
Loeb MB, Molloy DW, Smieja M, et al. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease. J Am Geriatr Soc. 2004 Mar;52(3):381-7.
Longpré F, et al. “Protection by EGb 761 against Beta-Amyloid-Induced Neurotoxicity: Involvement of NF-KappaB, SIRT1, and Mapks Pathways and Inhibition of Amyloid Fibril Formation.” Free Radic Biol Med. 41.12 (2006): 1781-94.
Lophatananon A, Mekli K, Cant R, et al. Shingles, Zostavax vaccination and risk of developing dementia: a nested case-control study-results from the UK Biobank cohort. BMJ Open. Oct 8 2021;11(10):e045871. doi:10.1136/bmjopen-2020-045871. https://bmjopen.bmj.com/content/bmjopen/11/10/e045871.full.pdf
Lu PH, Masterman DA, Mulnard R, et al. Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch Neurol. 2006 Feb;63(2):177-85.
Luan K, Rosales JL, Lee KY. “VIEWPOINT: Crosstalks Between Neurofibrillary Tangles and Amyloid Plaque Formation.” Ageing Res Rev. (2012) [Epub ahead of print]
Luchsinger JA, Cheng D, Tang MX, et al. Central obesity in the elderly is related to late-onset Alzheimer disease. Alzheimer Dis Assoc Disord. 2012 Apr;26(2): 101-5.
Lukiw WJ, et al. “A Role for Docosahexaenoic Acid-Derived Neuroprotectin D1 in Neural Cell Survival and Alzheimer Disease.” J Clin Invest. 115.10 (2005): 2774-83.
Luu-The V, Labrie F. “The Intracrine Sex Steroid Biosynthesis Pathways.” Prog Brain Res. 181. (2010): 177-92.
Lyketsos CG, Olin J. Depression in Alzheimer's disease: overview and treatment. Biological psychiatry. Aug 1 2002;52(3):243-252.
Ma QL, et al. “Beta-Amyloid Oligomers Induce Phosphorylation of Tau and Inactivation of Insulin Receptor Substrate via C-Jun N-Terminal Kinase Signaling: Suppression by Omega-3 Fatty Acids and Curcumin.” J Neurosci. 29.28 (2009): 9078-89.
MacMillan C. Lecanemab, the New Alzheimer's Treatment: 3 Things To Know. Yale Medicine. Updated 7/24/2023. Accessed 10/4/2024, https://www.yalemedicine.org/news/lecanemab-leqembi-new-alzheimers-drug
Magri F, Sarra S, Cinchetti W, et al. Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians. J Pineal Res. 2004 May;36(4):256-61.
Maki PM and Henderson VW. Hormone therapy, dementia, and cognition: the Women's Health Initiative 10 years on. Climacteric. 2012 Jun;15(3):256-62.
Mallajosyula JK, Chinta SJ, Rajagopalan S, Nicholls DG, Andersen JK. Metabolic control analysis in a cellular model of elevated MAO-B: relevance to Parkinson's disease. Neurotoxicity research.Oct 2009;16(3):186-193.
Malyka AG et al. Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders. Drugs. 2010 Feb 12;70(3):287-312.
Manacuso M, et al. “Coenzyme Q10 in Neuromuscular and Neurodegenerative Disorders.” Curr Drug Targets. 11.1 (2010): 111-21.
Mandel S, et al. “Green Tea Catechins as Brain-Permeable, Natural Iron Chelators-Antioxidants for the Treatment of Neurodegenerative Disorders.” Mol Nutr Food Res. 50.2 (2006): 229-34.
Mandel SA, et al. “Understanding the Broad-Spectrum Neuroprotective Action Profile of Green Tea Polyphenols in Aging and Neurodegenerative Diseases.” J Alzheimers Dis. 25.2 (2011): 187-208.
Manji HK, Moore GJ, Chen G. Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: implications for the pathophysiology and treatment of manic-depressive illness. Biological psychiatry.Oct 15 2000;48(8):740-754.
Maqbool M, et al. Pivotal role of glycogen synthase kinase-3: A therapeutic target for Alzheimer's disease. Eur J Med Chem. 2016;107: 63-81.
Marchesi VT. “Alzheimer’s disease 2012: the great amyloid gamble.” Am J Pathol. 180.5 (2012): 1762-7.
Markova N, et al. Thiamine and benfotiamine improve cognition and ameliorate GSK-3β-associated stress-induced behaviours in mice. Prog Neuropsychopharmacol Biol Psychiatry. 2017;75: 148-156.
Martin LJ. “Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases.” Pharmaceuticals (Basel). 3.4 (2010): 839-915.
Mas E, et al. “Functional Vitamin E Deficiency in ApoE4 Patients with Alzheimer’s Disease.” Dement Geriatr Cogn Disord. 21.3 (2006): 198-204.
Mashayekh A, et al. “Effects of Ginkgo biloba on Cerebral Blood Flow Assessed by Quantitative MR Perfusion Imaging: A Pilot Study.” Neuroradiology. 53.3 (2011): 185-91.
Massoud F, Gauthier S. Update on the pharmacological treatment of Alzheimer's disease. Curr Neuropharmacol. 2010 Mar;8(1):69-80.
Matsunaga S, et al. Lithium as a Treatment for Alzheimer's Disease: A Systematic Review and Meta-Analysis. J Alzheimers Dis. 2015;48(2): 403-410.
Mayo Clinic. Alzheimer’s disease. Definition. Available at: http://www.mayoclinic.com/health/alzheimers-disease/DS00161/. Last updated January 18, 2011. Accessed August 2, 2012.
Mayo P, Pascual J, Crisman E, Dominguez C, Lopez MG, Leon R. Innovative pathological network-based multitarget approaches for Alzheimer's disease treatment. Medicinal research reviews. Apr 28 2024;doi:10.1002/med.22045. https://pubmed.ncbi.nlm.nih.gov/38678582/
Mayo W, et al. “Individual Differences in Cognitive Aging: Implication of Pregnenolone Sulfate.” Prog Neurobiol. 2003 Sep;71(1):43-8.
Mayo W, et al. “Pregnenolone Sulfate Enhances Neurogenesis and PSA-NCAM in Young and Aged Hippocampus.” Neurobiol Aging. 2005 Jan;26(1):103-14.
McCann SM, et al. “The Nitric Oxide Theory of Aging Revisited.” Ann N Y Acad Sci. 1057 (2005): 64-84.
McDonnell DP, Connor CE, Wijayaratne A, et al. “Definition of the Molecular and Cellular Mechanisms Underlying the Tissue-selective Agonist/Antagonist Activities of Selective Estrogen Receptor Modulators.” Endocrine Reviews. 57.1 (2002): 295-316.
McShane R, Westby MJ, Roberts E, et al. Memantine as a treatment for dementia. Cochrane. Updated 3/20/2019. Accessed 9/5/2024, https://www.cochrane.org/CD003154/DEMENTIA_memantine-treatment-dementia
Mehta M, Adem A, and Sabbagh M. New Acetylcholinesterase Inhibitors for Alzheimer's Disease. Int J Alzheimers Dis. 2012;2012:728983.
Meng Q, Ru J, Zhang G, et al. Re-evaluation of tacrine hepatotoxicity using gel entrapped hepatocytes. Toxicol Lett. 2007 Jan 30;168(2):140-7.
Merighi S, Nigro M, Travagli A, Gessi S. Microglia and Alzheimer's Disease. Int J Mol Sci. Oct 27 2022;23(21)doi:10.3390/ijms232112990. https://pubmed.ncbi.nlm.nih.gov/36361780/
Miklossy J. Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria. J Neuroinflammation. 2011 Aug 4;8:90.
Milad SB, et al. “Inflammation and apoptosis in aortic tissues of aged type II diabetes: Amelioration with Mechanisms Underlying the Tissue-selective Agonist/Antagonist Activities of .” Life Sci. 86.23-24 (2010): 844-53.
Miller WL, “Androgen Biosynthesis from Cholesterol to DHEA.” Mol Cell Endocrinol. 198.1-2 (2002): 7-14.
Min JY, Min KB. Serum lycopene, lutein and zeaxanthin, and the risk of Alzheimer's disease mortality in older adults. Dement Geriatr Cogn Disord. 2014;37(3-4):246-256.
Mishra S, et al. “The Effect of Curcumin (Turmeric) on Alzheimer’s Disease: An Overview.” Ann Indian Acad Neurol. 11.1 (2008): 13-9.
Mizrahi EH, et al. “Plasma Total Homocysteine Levels, Dietary Vitamin B6 and Folate Intake in AD and Healthy Aging.” J Nutr Health Aging. 7.3 (2003): 160-5.
Moccetti T, Wullschleger C, Schmidt A, Aydogan C, Kreuter M. Bioactivity-based development of a wild green oat (Avena sativa L.) extract in support of mental health disorders. Zeitschrift für Phytotherapie.2006;27(S 1):P24.
Modrego PJ. Depression in Alzheimer's disease. Pathophysiology, diagnosis, and treatment. Journal of Alzheimer's disease : JAD. 2010;21(4):1077-1087.
Mold MJ, et al. Aluminum and Tau in Neurofibrillary Tangles in Familial Alzheimer’s Disease. Journal of Alzheimer's Disease Reports. 2021;5: 283-294.
Molloy DW, Standish TI, Zhou Q, Guyatt G. A multicenter, blinded, randomized, factorial controlled trial of doxycycline and rifampin for treatment of Alzheimer's disease: the DARAD trial. Int J Geriatr Psychiatry. 2013;28(5):463-470.
Montagnana M, et al. “Coffee Intake and Cardiovascular Disease: Virtue Does Not Take Center Stage.” Semin Thromb Hemos. 38.2 (2012): 164-77. Epub February 18, 2012.
Moreira PI, et al. “CoQ10 Therapy Attenuates Amyloid Beta-Peptide Toxicity in Brain Mitochondria Isolated from Aged Diabetic Rats.” Exp Neurol. 196.1 (2005): 112-9.
Moreira SC, Jansen AK, Silva FM. Dietary interventions and cognition of Alzheimer's disease patients: a systematic review of randomized controlled trial. Dementia & neuropsychologia. Jul-Sep 2020;14(3):258-282. doi:10.1590/1980-57642020dn14-030008. https://pubmed.ncbi.nlm.nih.gov/32973980/
Moreno M. “Cognitive improvement in mild to moderate Alzheimer’s dementia after treatment with the acetycholine precursor choline alfoscerate: A multicenter, double-blind, randomized, placebo-controlled trial.” Clin Ther. 25.1 (2003): 178-93.
Mori K, Inatomi S, Ouchi K, Azumi Y, Tuchida T. Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo-controlled clinical trial. Phytotherapy research : PTR. Mar 2009;23(3):367-372.
Morris MC, et al. “Dietary Niacin and the Risk of Incident Alzheimer’s Disease and of Cognitive Decline.” J Neurol Neurosurg Psychiatry. 75.8 (2004): 1093-9.
Motoko S, Motoko S, Kenichi Y, et al. Morphological and biochemical signs of age-related neurodegenerative changes in klotho mutant mice. Neuroscience. 2008;doi:10.1016/j.neuroscience.2008.01.032. https://pubmed.ncbi.nlm.nih.gov/18343589/
Mufson EJ, Counts SE, Perez SE, Ginsberg SD. Cholinergic system during the progression of Alzheimer's disease: therapeutic implications. Expert Rev Neurother. Nov 2008;8(11):1703-1718.
Mulder C, et al. “Low Vitamin B6 Levels Are Associated with White Matter Lesions in Alzheimer’s Disease.” J Am Geriatr Soc. 53.6 (2005): 1073-4.
Mullan K, Williams MA, Cardwell CR, et al. Serum concentrations of vitamin E and carotenoids are altered in Alzheimer's disease: A case-control study. Alzheimer's & dementia (New York, N Y). 2017;3(3):432-439.
Muller WE et al. Effects of piracetam on membrane fluidity in the aged mouse, rat, and human brain. Biochem Pharmacol. 1997 Jan 24;53(2):135-40.
Muñoz-Torrero D. Acetylcholinesterase inhibitors as disease-modifying therapies for Alzheimer's disease. Curr Med Chem. 2008;15(24):2433-55.
Murase K, et al. “Stimulation of Nerve Growth Factor Synthesis/Secretion in Mouse Astroglial Cells by Coenzymes.” Biochem Mol Biol Int. 30.4 (1993): 615-21.
Nagahara AH, et al. “Neuroprotective Effects of Brain-Derived Neurotrophic Factor in Rodent and Primate Models of Alzheimer’s Disease.” Nat Med. 15.3 (2009): 331-7.
Nagatsu T, Sawada M. Molecular mechanism of the relation of monoamine oxidase B and its inhibitors to Parkinson's disease: possible implications of glial cells. Journal of neural transmission. Supplementum. 2006(71):53-65.
Nakagawa K, Kiko T, Miyazawa T, Carpentero Burdeos G, Kimura F, Satoh A, Miyazawa T. Antioxidant effect of astaxanthin on phospholipid peroxidation in human erythrocytes. The British journal of nutrition. Jun 2011;105(11):1563-1571.
Nakano M, Ubukata K, Yamamoto T, Yamaguchi H. Effect of pyrroloquinoline quinone (PQQ) on mental status of middle-aged and elderly persons. FOOD Style. 2009;21:13(7):50-3.
Nath A. Herpes Viruses, Alzheimer's Disease, and Related Dementias: Unifying or Confusing Hypothesis? Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. Jan 2019;16(1):180-181. doi:10.1007/s13311-018-00701-4.
Ngandu T, Lehtisalo J, Solomon A, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. Jun 6 2015;385(9984):2255-63. doi:10.1016/S0140-6736(15)60461-5. https://pubmed.ncbi.nlm.nih.gov/25771249/
NICE. National Institute for Health and Care Excellence. Dementia: Assessment, management and support for people living with dementia and their carers. Ch. 11 - Cholinesterase inhibitors and memantine for dementia. Updated 6/2018. Accessed 9/5/2024. https://pubmed.ncbi.nlm.nih.gov/30011160/
Nielsen RE, Grøntved S, Lolk A, Andersen K, Valentin JB. Real-world effects of anti-dementia treatment on mortality in patients with Alzheimer´s dementia. Medicine (Baltimore). Nov 11 2022;101(45):e31625. doi:10.1097/md.0000000000031625. https://pubmed.ncbi.nlm.nih.gov/36397447/
Nieoullon A. [Acetylcholinesterase inhibitors in Alzheimer's disease: further comments on their mechanisms of action and therapeutic consequences]. Psychol Neuropsychiatr Vieil. 2010 Jun;8(2):123-31.
NLM. National Library of Medicine. DAILYMED. KINSUNLA - donanemab-azbt injection, solution. Updated 7/2/2024. Accessed 10/4/2024, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9d1ff786-e577-410a-a273-c4d7d0e4e975
NLM. National Library of Medicine. DAILYMED. LEQEMBI - lecanemab injection, solution. Drug Label Information. Updated 7/22/2023. Accessed 10/4/2024, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9d1ff786-e577-410a-a273-c4d7d0e4e975
Nolan JM, Loskutova E, Howard A, et al. The impact of supplemental macular carotenoids in Alzheimer's disease: a randomized clinical trial. J Alzheimers Dis. 2015;44(4):1157-1169.
Nolan JM, Mulcahy R, Power R, Moran R, Howard AN. Nutritional Intervention to Prevent Alzheimer's Disease: Potential Benefits of Xanthophyll Carotenoids and Omega-3 Fatty Acids Combined. J Alzheimers Dis. 2018;64(2):367-378.
Nolan JM, Power R, Howard AN, et al. Supplementation With Carotenoids, Omega-3 Fatty Acids, and Vitamin E Has a Positive Effect on the Symptoms and Progression of Alzheimer's Disease. J Alzheimers Dis. 2022;90(1):233-249. doi:10.3233/JAD-220556. https://pubmed.ncbi.nlm.nih.gov/36093704/
Nunes MA, Viel TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer's disease. Current Alzheimer research.Jan 2013;10(1):104-107.
Nunes PV, et al. “Lithium and Risk for Alzheimer’s Disease in Elderly Patients with Bipolar Disorder.” Br J Psychiatry. 190 (2007): 359-60.
O’Neill, et al. “Impact of the Selective Estrogen Receptor Modulator, Tamoxifen, on Neuronal Outgrowth and Survival following Toxic Insults Associated with Aging and Alzheimer’s disease.” Exp Neurol. 2004 Aug;188(2):268-78.
Ono K, et al. “Preformed Beta-Amyloid Fibrils Are Destabilized by Coenzyme Q10 in Vitro.” Biochem Biophys Res Commun. 330.1 (2005): 111-6.
Ornish D, Madison C, Kivipelto M, et al. Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer's disease: a randomized, controlled clinical trial. Alzheimers Res Ther. Jun 7 2024;16(1):122. doi:10.1186/s13195-024-01482-z. https://pubmed.ncbi.nlm.nih.gov/38849944/
Overk CR, Perez SE, Ma C, et al. Sex Steroid Levels and Ad-Like Pathology in 3xtgad Mice. [In Eng] J Neuroendocrinol. 2012 Aug 13;
Pan L, Zhou Y, Li XF, Wan QJ, Yu LH. Preventive treatment of astaxanthin provides neuroprotection through suppression of reactive oxygen species and activation of antioxidant defense pathway after stroke in rats. Brain research bulletin. Apr 2017;130:211-220.
Pan X, et al. Long-Term Cognitive Improvement After Benfotiamine Administration in Patients with Alzheimer's Disease. Neurosci Bull. 2016;32(6): 591-596.
Pangalos MN, et al. “Drug Development for CNS Disorders: Strategies for Balancing Risk and Reducing Attrition.” Nat Rev Drug Discov. 6 (2007): 521-32.
Park HA, Hayden MM, Bannerman S, Jansen J, Crowe-White KM. Anti-Apoptotic Effects of Carotenoids in Neurodegeneration. Molecules (Basel, Switzerland). 2020;25(15).
Parletta N, Milte CM, Meyer BJ. Nutritional modulation of cognitive function and mental health. The Journal of nutritional biochemistry. May 2013;24(5):725-743.
Pasinetti GM, Zhao Z, Qin W, et al. Caloric intake and Alzheimer's disease. Experimental approaches and therapeutic implications. Interdiscip Top Gerontol. 2007;35:159-75.
Pereira C, et al. “Neuroprotection Strategies: Effect of Vinpocetine in Vitro Oxidative Stress Models” [in Portuguese]. Acta Med Port. 16.6 (2003): 401-6.
Perry EK, et al. “Medicinal Plants and Alzheimer’s Disease: From Ethnobotany to Phytotherapy.” J Pharm Pharmacol. 51.5 (1999): 527-34.
Pettegrew JW, et al. “Clinical and Neurochemical Effects of Acetyl-L-Carnitine in Alzheimer’s disease.” Neurobiol Aging. 16.1 (1995) 1-4.
Phan CW, Lee GS, Hong SL, Wong YT, Brkljaca R, Urban S, . . . Sabaratnam V. Hericium erinaceus (Bull.: Fr) Pers. cultivated under tropical conditions: isolation of hericenones and demonstration of NGF-mediated neurite outgrowth in PC12 cells via MEK/ERK and PI3K-Akt signaling pathways. Food Funct. Dec 2014;5(12):3160-3169.
Pocernich CB, et al. “In Vivo Glutathione Elevation Protects against Hydroxyl Free Radical-Induced Protein Oxidation in Rat Brain.” Neurochem Int. 36.3 (2000): 185-91.
Pocernich CB, et al. “Nutritional Approaches to Modulate Oxidative Stress in Alzheimer’s Disease.” Curr Alzheimer Res. 8.5 (2011): 452-69.
Poeckel D, Funk CD. The 5-lipoxygenase/leukotriene pathway in preclinical models of cardiovascular disease. Cardiovascular research. May 1 2010;86(2):243-253.
Polleri A, et al. “Dementia: A Neuroendocrine Perspective.” J Endocrinol Invest. 25.1 (2002): 73-83.
Polvikoski T, Sulkava R, Haltia M, et al. Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. N Engl J Med. 1995 Nov 9;333(19):1242-7.
Power R, Coen RF, Beatty S, et al. Supplemental Retinal Carotenoids Enhance Memory in Healthy Individuals with Low Levels of Macular Pigment in A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. J Alzheimers Dis. 2018;61(3):947-961.
Press D, Alexander M. Cholinesterase inhibitors in the treatment of dementia. UpToDate. Updated 5/28/2024. Accessed 9/5/2024, https://www.uptodate.com/contents/cholinesterase-inhibitors-in-the-treatment-of-dementia
Press D, Buss SS. Treatment of Alzheimer disease. UpToDate. Updated 9/30/2021. Accessed 9/5/2024, https://www.uptodate.com/contents/treatment-of-alzheimer-disease
Prud'homme GJ, Kurt M, Wang Q. Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations. Front Aging. 2022;3:931331. doi:10.3389/fragi.2022.931331. https://pubmed.ncbi.nlm.nih.gov/35903083/
Qiu C, et al. “Vascular and Psychosocial Factors in Alzheimer’s Disease: Epidemiological Evidence toward Intervention.” J Alzheimers Dis. 20.3 (2010): 689-97.
Qiu C. Preventing Alzheimer's Disease by Targeting Vascular Risk Factors: Hope and Gap. J Alzheimers Dis. 2012 Jul 27. [Epub ahead of print]
Quadri P, et al. “Homocysteine and B Vitamins in Mild Cognitive Impairment and Dementia.” Clin Chem Lab Med. 43.10 (2005): 1096-100.
Rafii MS, Walsh S, Little JT, et al. A phase II trial of huperzine A in mild to moderate Alzheimer disease. Neurology. 2011 Apr 19;76(16):1389-94.
Rahman SO, Panda BP, Parvez S, et al. Neuroprotective role of astaxanthin in hippocampal insulin resistance induced by Abeta peptides in animal model of Alzheimer's disease. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2019;110:47-58.
Ramirez A and Arbuckle MR. Synaptic Plasticity: The Role of Learning and Unlearning in Addiction and Beyond. Biol Psychiatry. 2016;80(9): e73-e75.
Ravaglia G, et al. “Homocysteine and Folate as Risk Factors for Dementia and Alzheimer Disease.” Am J Clin Nutr. 82.3 (2005): 636-43.
Remington R, Bechtel C, Larsen D, et al. A Phase II Randomized Clinical Trial of a Nutritional Formulation for Cognition and Mood in Alzheimer's Disease. J Alzheimers Dis. 2015;45(2):395-405. doi:10.3233/JAD-142499. https://pubmed.ncbi.nlm.nih.gov/25589719/
Renzi LM, Dengler MJ, Puente A, Miller LS, Hammond BR, Jr. Relationships between macular pigment optical density and cognitive function in unimpaired and mildly cognitively impaired older adults. Neurobiol Aging. 2014;35(7):1695-1699.
Rex A, Spychalla M, Fink H. Treatment with reduced nicotinamide adenine dinucleotide (NADH) improves water maze performance in old Wistar rats. Behavioural brain research.Sep 23 2004;154(1):149-153.
Rezai-Zadeh K, et al. “Flavonoid-Mediated Presenilin-1 Phosphorylation Reduces Alzheimer’s Disease Beta-Amyloid Production.” J Cell Mol Med. 13.3 (2009): 574-88.
Rezai-Zadeh K, et al. “Green Tea Epigallocatechin-3-Gallate (EGCG) Modulates Amyloid Precursor Protein Cleavage and Reduces Cerebral Amyloidosis in Alzheimer Transgenic Mice.” J Neurosci. 25.38 (2005): 8807-14.
Rezai-Zadeh K, et al. “Green Tea Epigallocatechin-3-Gallate (EGCG) Reduces Beta-Amyloid Mediated Cognitive Impairment and Modulates Tau Pathology in Alzheimer Transgenic Mice.” Brain Res. 12.1214 (2008): 177-87.
Richard T, et al. “Neuroprotective Properties of Resveratrol and Derivatives.” Ann N Y Acad Sci. 1215 (2011): 103-8.
Richter Y, et al. “The Effect of Phosphatidylserine-containing Omega-3 Fatty Acids on Memory Abilities in Subjects with Subjective Memory Complaints: A Pilot Study.” Clin Interv Aging. 5 (2010): 313-6.
Ringman JM, et al. “A Potential Role of the Curry Spice Curcumin in Alzheimer’s Disease.” Curr Alzheimer Res. 2.2 (2005): 131-6.
Rockenstein E, Torrance M, Adame A, et al. Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer's disease are associated with reduced amyloid precursor protein phosphorylation. The Journal of neuroscience: the official journal of the Society for Neuroscience. Feb 21 2007;27(8):1981-1991.
Rosales-Corral SA, et al. “Alzheimer’s Disease: Pathological Mechanisms and the Beneficial Role of Melatonin.” J Pineal Res. 52.2 (2012): 167-202.
Rosenberg A, Ngandu T, Rusanen M, et al. Multidomain lifestyle intervention benefits a large elderly population at risk for cognitive decline and dementia regardless of baseline characteristics: The FINGER trial. Alzheimers Dement. Mar 2018;14(3):263-270. doi:10.1016/j.jalz.2017.09.006. https://pubmed.ncbi.nlm.nih.gov/29055814/
Rusanen M, Solomon A, et al. Effect of a multi-domain lifestyle intervention on cardiovascular risk in older people: the FINGER trial. Eur Heart J. Jun 1 2022;43(21):2054-2061. doi:10.1093/eurheartj/ehab922. https://pubmed.ncbi.nlm.nih.gov/35051281/
Rybakowski JK. Effect of Lithium on Neurocognitive Functioning. Current Alzheimer research.2016;13(8):887-893.
Sadowsky CH, Galvin JE. “Guidelines for management of cognitive and behavioral problems in dementia.” J Am Board Fam Med. 25.3 (2012): 350-66.
Saito ER, et al. Alzheimer's disease alters oligodendrocytic glycolytic and ketolytic gene expression. Alzheimer's & Dementia. 2021 Mar 2 [Online ahead of print]. https://pubmed.ncbi.nlm.nih.gov/33650792/
Salminen A, et al. “Inflammation in Alzheimer’s disease: Amyloid-β Oligomers Trigger Innate Immunity Defence via Pattern Recognition Receptors.” Prog Neurobiol. 87.3 (2009):181-194.
Sanchez PE, Zhu L, Verret L, et al. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model. Proc Natl Acad Sci U S A. 2012 Aug 6. [Epub ahead of print]
Sasaki Y, Araki T, Milbrandt J. Stimulation of nicotinamide adenine dinucleotide biosynthetic pathways delays axonal degeneration after axotomy. The Journal of neuroscience: the official journal of the Society for Neuroscience.Aug 16 2006;26(33):8484-8491.
Sastre M, Gentleman SM. NSAIDs: How they Work and their Prospects as Therapeutics in Alzheimer's Disease. Front Aging Neurosci. 2010 May 18;2:20.
Satoh A, Tsuji S, Okada Y, Murakami N, Urami M, Nakagawa K, . . . Shirasawa T. Preliminary Clinical Evaluation of Toxicity and Efficacy of A New Astaxanthin-rich Haematococcus pluvialis Extract. Journal of clinical biochemistry and nutrition. May 2009;44(3):280-284.
Saura J, Luque JM, Cesura AM, Da Prada M, Chan-Palay V, Huber G, Löffler J, Richards JG. Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. Neuroscience.Sep 1994;62(1):15-30.
Scarmeas N, et al. “Mediterranean Diet and Alzheimer Disease Mortality.” Neurology. 69 (2007): 1084-93.
Scarmeas N, et al. “Mediterranean Diet and Mild Cognitive Impairment.” Arch Neurol. 66.2 (2009): 216-25.
Scherrer J, Salas J, Jacobs C, Wiemken T. Lower dementia risk in patients vaccinated against herpes zoster. Ann Fam Med. Apr 1 2022;(20 Suppl 1)https://pubmed.ncbi.nlm.nih.gov/36696249/
Schmitz C, et al. “Hippocampal Neuron Loss Exceeds Amyloid Plaque Load in a Transgenic Mouse Model of Alzheimer’s Disease.” Am J Pathol. 2004 Apr;164(4):1495-502.
Schneider LS, et al. “A Randomized, Double-Blind, Placebo-Controlled Trial of Two Doses of Ginkgo biloba Extract in Dementia of the Alzheimer’s Type.” Curr Alzheimer Res. 2.5 (2005): 541-51.
Schreiber S, et al. “An Open Trial of Plant-Source Derived Phosphatydilserine for Treatment of Age-Related Cognitive Decline.” Isr J Psychiatry Relat Sci. 37.4 (2000): 302-7.
Schulte-Herbrüggen O, Jockers-Scherübl MC, Hellweg R. Neurotrophins: from pathophysiology to treatment in Alzheimer's disease. Curr Alzheimer Res. 2008 Feb;5(1):38-44.
Schumacher M, et al. “Local Synthesis and Dual Actions of Progesterone in the Nervous System: Neuroprotection and Myclination.” Growth Horm IGF Res. 14.A (2004):S18-33.
Schuster D, Rajendran A, Hui SW, Nicotera T, Srikrishnan T, Kruzel ML. Protective effect of colostrinin on neuroblastoma cell survival is due to reduced aggregation of beta-amyloid. Neuropeptides.Aug 2005;39(4):419-426.
Sehgal N, Gupta A, Valli RK,et al. Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3510-5. Epub 2012 Jan 30.
Senin U, Parnetti L, Barbagallo-Sangiorgi G, et al. Idebenone in Senile Dementia of Alzheimer Type: A Multicentre Study. [In eng] Arch Gerontol Geriatr. 1992 Nov-Dec; 15(3): 249-60.
Semba RD, Moghekar AR, Hu J, et al. Klotho in the cerebrospinal fluid of adults with and without Alzheimer's disease. Neurosci Lett. Jan 13 2014;558:37-40. doi:10.1016/j.neulet.2013.10.058. https://pubmed.ncbi.nlm.nih.gov/24211693/
Serot JM, et al. “CSF-Folate Levels Are Decreased in Late-Onset AD Patients.” J Neural Transm. 108.1 (2001): 93-9.
Servick K. Alzheimer's drug approved despite doubts about effectiveness: FDA breaks from advisers to clear Aduhelm based on reduction of toxic brain plaques. Updated 6/7/2021. Accessed 9/5/2024, https://www.science.org/content/article/alzheimer-s-drug-approved-despite-doubts-about-effectiveness
Shah NS, Vidal JS, Masaki K. Midlife blood pressure, plasma β-amyloid, and the risk for Alzheimer disease: the Honolulu Asia Aging Study. Hypertension. 2012 Apr;59(4):780-6. Epub 2012 Mar 5.
Shi J, et al. “Polyphenolics in Grape Seeds: Biochemistry and Functionality.” J Med Food. 6.4 (2003): 291-9.
Shireen KF, et al. “Effects of Dietary Vitamin E, C and Soybean Oil Supplementation on Antioxidant Enzyme Activities in Liver and Muscles of Rats.” Food Chem Toxicol. 46.10 (2008): 3290-3294.
Shyh-Hwa L, et al. “Docosahexaenoic Acid and Phosphatidylserine Supplementations Improve Antioxidant Activities and Cognitive Functions of the Developing Brain on Pentylenetetrazol-Induced Seizure Model.” Brain Res. 1451. (2012): 19-26.
Sifi N, Martin-Eauclaire MF, Laraba-Djebari F. K(+) channel blocker-induced neuroinflammatory response and neurological disorders: immunomodulatory effects of astaxanthin. Inflammation research : official journal of the European Histamine Research Society ... [et al.]. Aug 2016;65(8):623-634.
Silva BC, de Miranda AS, Rodrigues FG, Silveira AL, Resende GH, Moraes MF, . . . Rachid MA. The 5-lipoxygenase (5-LOX) Inhibitor Zileuton Reduces Inflammation and Infarct Size with Improvement in Neurological Outcome Following Cerebral Ischemia. Current neurovascular research. 2015;12(4):398-403.
Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512-527. doi:10.1001/jama.2023.13239. https://pubmed.ncbi.nlm.nih.gov/37459141/
Singhaarachchi PH, Antal P, Calon F, et al. Aging, sex, metabolic and life experience factors: Contributions to neuro-inflammaging in Alzheimer's disease research. Neuroscience and biobehavioral reviews. Jul 2024;162:105724. doi:10.1016/j.neubiorev.2024.105724. https://pubmed.ncbi.nlm.nih.gov/38762130/
Singhrang N, Tocharus C, Thummayot S, Sutheerawattananonda M, Tocharus J. Protective effects of silk lutein extract from Bombyx mori cocoons on beta-Amyloid peptide-inducedapoptosis in PC12 cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2018;103:582-587.
Sitges M, et al. “Vinpocetine Blockade of Sodium Channels Inhibits the Rise in Sodium and Calcium Induced by 4-Aminopyridine in Synaptosomes.” Neurochem Int. 46.7 (2005): 533-40.
Slutsky I, et al. “Enhancement of Learning and Memory by Elevating Brain Magnesium.” Neuron. 65.2 (2010): 165-77.
Soininen H, Solomon A, Visser PJ, et al. 24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial. Lancet Neurol. Dec 2017;16(12):965-975. doi:10.1016/S1474-4422(17)30332-0. https://pubmed.ncbi.nlm.nih.gov/29097166/
Soininen H, Solomon A, Visser PJ, et al. 36-month LipiDiDiet multinutrient clinical trial in prodromal Alzheimer's disease. Alzheimers Dement. Jan 2021;17(1):29-40. doi:10.1002/alz.12172. https://pubmed.ncbi.nlm.nih.gov/32920957/
Solomon A, Turunen H, Ngandu T, et al. Effect of the Apolipoprotein E Genotype on Cognitive Change During a Multidomain Lifestyle Intervention: A Subgroup Analysis of a Randomized Clinical Trial. JAMA Neurol. Apr 1 2018;75(4):462-470. doi:10.1001/jamaneurol.2017.4365. https://pubmed.ncbi.nlm.nih.gov/29356827/
Solfrizzi V, et al. “Mediterranean Diet in Predementia and Dementia Syndromes.” Curr Alzheimer Res. 2011 Aug;8(5):520-42.
Soscia SJ, Kirby JE, Washicosky KJ, et al. The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One. 2010 Mar 3;5(3):e9505.
Sostres C, Gargallo CJ, Arroyo MT, et al. “Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract.” Best Prac Res Clin Gastroenterol. 24.2 (2010):121-32.
Srinivasan V, et al. “Melatonin in Alzheimer’s Disease and Other Neurodegenerative Disorders.” Behav Brain Funct. 4.2 (2006): 15.
Srivastava S. Emerging therapeutic roles for NAD(+) metabolism in mitochondrial and age-related disorders. Clinical and translational medicine.Dec 2016;5(1):25.
St. George-Hyslop PH, et al. “Will Anti-Amyloid Therapies Work for Alzheimer’s Disease?” Lancet. 2008 Jul 19;372(9634):180-2.
Stern: Massachusetts General Hospital Comprehensive Clinical Psychiatry, 1st ed. Copyright © 2008 Mosby, An Imprint of Elsevier. Available at http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-0-323-04743-2..50021-4--cesec5&isbn=978-0-323-04743-2&uniqId=348489237-3#4-u1.0-B978-0-323-04743-2..50021-4--cesec5 Accessed 7/31/2012.
Stewart MG. Colostrinin: a naturally occurring compound derived from mammalian colostrum with efficacy in treatment of neurodegenerative diseases, including Alzheimer's. Expert opinion on pharmacotherapy.Oct 2008;9(14):2553-2559.
Suchy J, et al. “Dietary supplementation with a combination of α-lipoic acid, acetyl-l-carnitine, glycerophosphocoline, docosahexaenoic acid, and phosphatidylserine reduces oxidative damage to murine brain and improves cognitive performance.” Nut Res. 29.1 (2009): 70-74.
Sun QQ, et al. “Huperzine-A Capsules Enhance Memory and Learning Performance in 34 Pairs of Matched Adolescent Students.” Zhongguo Yao Li Xue Bao. 20.7 (1999): 601-3.
Sun XJ, et al. Benfotiamine prevents increased β-amyloid production in HEK cells induced by high glucose. Neurosci Bull. 2012;28(5): 561-566.
Swanson D, et al. “Omega-3 fatty acids DHA and EPA: Health Benefits throughout Life.” Adv Nutr. 3.1 (2012): 1-7
Szilagyi G, et al. “Effects of Vinpocetine on the Redistribution of Cerebral Blood Flow and Glucose Metabolism in Chronic Ischemic Stroke Patients: A PET Study.” J Neurol Sci. Mar 15 (2005); 229-230: 275-84.
Taksima T, Chonpathompikunlert P, Sroyraya M, Hutamekalin P, Limpawattana M, Klaypradit W. Effects of Astaxanthin from Shrimp Shell on Oxidative Stress and Behavior in Animal Model of Alzheimer's Disease. Mar Drugs. 2019;17(11).
Tan WF, Cao XZ, Wang JK, Lv HW, Wu BY, Ma H. Protective effects of lithium treatment for spatial memory deficits induced by tau hyperphosphorylation in splenectomized rats. Clinical and experimental pharmacology & physiology.Oct 2010;37(10):1010-1015.
Tao R, et al. “Pyrroloquinoline quinone preserves mitochondrial function and prevents oxidative injury in Alzheimer’s diseaseult rat cardiac myocytes.” Biochem Biophys Res Commune. 363.2 (2007):257-262. Epub ahead of printTarawneh R and Holtzman DM. The clinical problem of symptomatic Alzheimer disease and mild cognitive impairment. Cold Spring Harb Perspect Med. 2012;2(5):a006148.
Tarawneh R, Holtzman DM. “The clinical problem of symptomatic Alzheimer disease and mild cognitive impairment.” Cold Spring Harb Perspect Med. 2.5 (2012):a006148.
Taquet M, Dercon Q, Todd JA, Harrison PJ. The recombinant shingles vaccine is associated with lower risk of dementia. Nat Med. 2024; 30(10): 2777-2781. doi:10.1038/s41591-024-03201-5. https://pubmed.ncbi.nlm.nih.gov/39053634/
Tchantchou F, et al. “N-Acetyl Cysteine Alleviates Oxidative Damage to Central Nervous System of Apoe-Deficient Mice Following Folate and Vitamin E-Deficiency.” J Alzheimers Dis. 7.2 (2005): 135-8.
Teng CC, Yang YT, Chen YC, et al. “Role of WWOX/WOX1 in Alzheimer’s disease pathology and in cell death signaling.” Front Biosci (Elite Ed). 4 (2012): 1951-65.
Theendakara V, et al. Transcriptional Effects of ApoE4: Relevance to Alzheimer's Disease. Mol Neurobiol. 2018;55(6): 5243-5254.
Tobinick EL and Gross H. “Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration.” J Neuroinflammation. 5 (2008b): 2.
Tobinick EL and Gross H. “Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer’s disease.” BMC Neurol. 8 (2008a): 27.
Tobinick EL. “Deciphering the Physiology Underlying the Rapid Clinical Effects of Perispinal Etanercept in Alzheimer’s disease.” Curr Alzheimer Res. 9.1 (2012): 99-109.
Tomljenovic L. Aluminum and Alzheimer's disease: after a century of controversy, is there a plausible link? J Alzheimers Dis. 2011;23(4): 567-598.
Trenkwalder P. “The Study on Cognition and Prognosis in the Elderly (SCOPE)—Recent Analyses.” J Hypertens Suppl. 24.1 (2006): S107-14.
Truebinding Inc. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT05074498. Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of TB006 in Participants with Alzheimer's Disease. Updated 11/18/2023. Accessed 10/8/2024, https://clinicaltrials.gov/study/NCT05074498
TrueBinding. Expanded Access Program (EAP) for TB006. Accessed 9/13/2024a, https://www.truebinding.com/expanded-access
TrueBinding. TB006, a humanized monoclonal antibody targeting Galectin-3, is a potentially revolutionary drug for Alzheimer's Disease treatment. Accessed 10/8/2024b, https://www.truebinding.com/ourscience
Truong C, Recto C, Lafont C, Canoui-Poitrine F, Belmin JB, Lafuente-Lafuente C. Effect of Cholinesterase Inhibitors on Mortality in Patients With Dementia: A Systematic Review of Randomized and Nonrandomized Trials. Neurology. Nov 14 2022;99(20):e2313-e2325. doi:10.1212/wnl.0000000000201161. https://pubmed.ncbi.nlm.nih.gov/36096687/
Tsai GE, k WE, Gunther J, et al. Improved cognition in Alzheimer's disease with short-term D-cycloserine treatment. Am J Psychiatry. 1999 Mar;156(3):467-9.
Tsai KJ, et al. “G-CSF Rescues the Memory Impairment of Animal Models of Alzheimer’s Disease.” J Exp Med. 204.6 (2007): 1273-80.
Tsai-Teng T, Chin-Chu C, Li-Ya L, Wan-Ping C, Chung-Kuang L, Chien-Chang S, . . . Shiao YJ. Erinacine A-enriched Hericium erinaceus mycelium ameliorates Alzheimer's disease-related pathologies in APPswe/PS1dE9 transgenic mice. J Biomed Sci. Jun 27 2016;23(1):49.
Tsaltas E, Kontis D. [A review of the effects of lithium on cognitive functions: Effects on the neuropsychiatrically challenged CNS]. Psychiatrike = Psychiatriki.Apr 2009;20(2):132-144.
Tu XK, Zhang HB, Shi SS, Liang RS, Wang CH, Chen CM, Yang WZ. 5-LOX Inhibitor Zileuton Reduces Inflammatory Reaction and Ischemic Brain Damage Through the Activation of PI3K/Akt Signaling Pathway. Neurochemical research. Oct 2016;41(10):2779-2787.
Tucker KL, et al. “High Homocysteine and Low B Vitamins Predict Cognitive Decline in Aging Men: The Veterans Affairs Normative Aging Study.” Am J Clin Nutr. 82.3 (2005): 627-35.
Twarowski B, Herbet M. Inflammatory Processes in Alzheimer's Disease-Pathomechanism, Diagnosis and Treatment: A Review. Int J Mol Sci. Mar 30 2023;24(7)doi:10.3390/ijms24076518. https://pubmed.ncbi.nlm.nih.gov/37047492/
Tzeng TT, Chen CC, Chen CC, Tsay HJ, Lee LY, Chen WP, . . . Shiao YJ. The Cyanthin Diterpenoid and Sesterterpene Constituents of Hericium erinaceus Mycelium Ameliorate Alzheimer's Disease-Related Pathologies in APP/PS1 Transgenic Mice. International journal of molecular sciences. Feb 17 2018;19(2).
Ukraintseva S, Yashkin A, Duan M, et al. Repurposing of existing vaccines for personalized prevention of Alzheimer’s disease: Vaccination against pneumonia may reduce AD risk depending on genotype: Genetics/genetic factors of Alzheimer's disease. Alzheimer's & Dementia. 12/01 2020;16doi:10.1002/alz.046751. https://alz-journals.onlinelibrary.wiley.com/doi/abs/10.1002/alz.046751
Upadhyaya P, Seth V, Ahmad M. “Therapy for Alzheimer’s disease: An update.” African Journal of Pharmacy and Pharmacology. 4.6 (2010): 408-21.
Uzun S, Kozumplik O, Folnegovic-Smalc V. “Alzheimer’s Dementia: Current Data Review.” Coll Antropol. 2011 Dec;35(4):1333-7.
Vagnozzi AN, Giannopoulos PF, Pratico D. The direct role of 5-lipoxygenase on tau pathology, synaptic integrity and cognition in a mouse model of tauopathy. Translational psychiatry. Dec 18 2017;7(12):1288.
Van der Auwera I, Wera S, Van Leuven F, et al. “A ketogenic diet reduces amyloid beta 40 and 42 in mouse model of Alzheimer’s disease.” Nutr Metab (Lond). 2 (2005):28.
van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med. Jan 5 2023;388(1):9-21. doi:10.1056/NEJMoa2212948. https://pubmed.ncbi.nlm.nih.gov/36449413/
van Himbergen TM, et al. “Biomarkers for Insulin Resistance and Inflammation and the Risk for All-Cause Dementia and Alzheimer Disease: Results From the Framingham Heart Study.” Arch Neurol. (2012): Epub ahead of print January 2, 2012. doi:10.1001/archneurol.2011.670.
van Praag H. “Exercise and the Brain: Something to Chew On.” Trends Neurosci. 32.5 (2009): 283-90.
Ven Murthy MR, et al. “Scientific Basis for the Use of Indian Ayurvedic Medicinal Plants in the Treatment of Neurodegenerative Disorders: Ashwagandha.” Cent Nerv Syst Agents Med Chem. 10.3 (2010): 238-46.
Vest RS, and Pike CJ. Gender, sex steroid hormones, and Alzheimer's disease. Horm Behav. 2012 Apr 19. [Epub ahead of print]
Vingtdeux V, Dreses-Werringloer U, Zhao H, et al. “Therapeutic potential of resveratrol in Alzheimer’s disease.” BMC Neurosci. 9(Suppl 2) (2008): S6.
Virmani MA, et al. “The Action of Acetyl-L-Carnitine on the Neurotoxicity Evoked by Amyloid Fragments and Peroxide on Primary Rat Cortical Neurones.” Ann N Y Acad Sci. 939 (2001): 162-78.
Waegemans T et al. Clinical efficacy of piracetam in cognitive impairment: a meta-analysis. Dement Geriatr Cogn Disord. 2002;13(4):217-24.
Walker D, et al. “Anti-Inflammatory and Immune Therapy for Alzheimer’s Disease: Current Status and Future Directions.” Curr Neuropharmacol. 5.4 (2007): 232-43.
Walter A, et al. “ Glycerophosphocholine is Elevated in Cerebrospinal Fluid of Alzheimer Patients.” Neurobiol Aging. 25.10 (2004): 1299-303.
Wang BS, et al. “Efficacy and Safety of Natural Acetylcholinesterase Inhibitor Huperzine A in the Treatment of Alzheimer’s Disease: An Updated Meta-Analysis.” J Neural Transm. 116.4 (2009): 457-65.
Wang HX, et al. “Vitamin B(12) and Folate in Relation to the Development of Alzheimer’s Disease.” Neurology. 56.9 (2001): 1188-94.
Wang J, et al. “Grape-Derived Polyphenolics Prevent Alpha Beta Oligomerization and Attenuate Cognitive Deterioration in a Mouse Model of Alzheimer’s Disease.” J Neurosci. 28.25 (2008): 6388-92.
Wang JZ, et al. “Role of Melatonin in Alzheimer-Like Neurodegeneration.” Acta Pharmacol Sin. 27.1 (2006a): 41-9.
Wang R, et al. “Progress in Studies of Huperzine A: A Natural Cholinesterase Inhibitor from Chinese Herbal Medicine.” Acta Pharmacol Sin. 27.1 (2006b): 1-26.
Wang X, Su B, Perry G, et al. Insights into amyloid-beta-induced mitochondrial dysfunction in Alzheimer disease. Free Radic Bio Med. 43.12 (2007): 1569-73.
Wang XD, Zhang JM, Yang HH, et al. Modulation of NMDA receptor by huperzine A in rat cerebral cortex. Zhongguo Yao Li Xue Bao. 1999 Jan;20(1):31-5.
Warren-Gash C, Forbes HJ, Williamson E, et al. Human herpesvirus infections and dementia or mild cognitive impairment: a systematic review and meta-analysis. Sci Rep. Mar 18 2019;9(1):4743. doi:10.1038/s41598-019-41218-w. https://www.nature.com/articles/s41598-019-41218-w.pdf
Watkins PB, Dube LM, Walton-Bowen K, Cameron CM, Kasten LE. Clinical pattern of zileuton-associated liver injury: results of a 12-month study in patients with chronic asthma. Drug safety. 2007;30(9):805-815.
Weill-Engerer S, et al. “Neurosteroid Quantification in Human Brain Regions: Comparison between Alzheimer’s and Nondemented Patients.” J Clin Endocrinol Metab. 87.11 (2002): 5138-43.
William BW, Cruz C. “Impact of NSAIDs on Cardiovascular Risk and Hypertension.” Ital J Med. 5.3 (2011):175-183.
Winter B et al. High impact running improves learning. Neurobiol Learn Mem. 2007 May;87(4):597-609.
Withington CG, Turner RS. Amyloid-Related Imaging Abnormalities With Anti-amyloid Antibodies for the Treatment of Dementia Due to Alzheimer's Disease. Front Neurol. 2022;13:862369. doi:10.3389/fneur.2022.862369. https://pubmed.ncbi.nlm.nih.gov/35401412/
Won E. and Kim Y-K. An Oldie but Goodie: Lithium in the Treatment of Bipolar Disorder through Neuroprotective and Neurotrophic Mechanisms. International journal of molecular sciences. 2017;18(12): 2679.
Wong KH, Kanagasabapathy G, Naidu M, David P, Sabaratnam V. Hericium erinaceus (Bull.: Fr.) Pers., a medicinal mushroom, activates peripheral nerve regeneration. Chin J Integr Med. Oct 2016;22(10):759-767.
Wong RH, Howe PR, Bryan J, Coates AM, Buckley JD, Berry NM. Chronic effects of a wild green oat extract supplementation on cognitive performance in older adults: a randomised, double-blind, placebo-controlled, crossover trial. Nutrients.May 2012;4(5):331-342.
Wu A, et al. “Dietary Omega-3 Fatty Acids Normalize BDNF Levels, Reduce Oxidative Damage, and Counteract Learning Disability after Traumatic Brain Injury in Rats.” J Neurotrauma. 21.10 (2004a): 1457-67.
Wu H, Niu H, Shao A, Wu C, Dixon BJ, Zhang J, . . . Wang Y. Astaxanthin as a Potential Neuroprotective Agent for Neurological Diseases. Marine drugs. Sep 11 2015;13(9):5750-5766.
Wu Q, Zhang XS, Wang HD, Zhang X, Yu Q, Li W, . . . Wang XL. Astaxanthin activates nuclear factor erythroid-related factor 2 and the antioxidant responsive element (Nrf2-ARE) pathway in the brain after subarachnoid hemorrhage in rats and attenuates early brain injury. Marine drugs. Dec 18 2014;12(12):6125-6141.
Wu X, et al. “Lipophilic and Hydrophilic Antioxidant Capacities of Common Foods in the United States.” J Agric Food Chem. 52.12 (2004b): 4026-37.
Xiong MH, et al. APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function. Sci Transl Med. 2021;13(581).
Xiong X, Hu T, Yin Z, et al. Research advances in the study of sleep disorders, circadian rhythm disturbances and Alzheimer's disease. Front Aging Neurosci. 2022;14:944283. https://pubmed.ncbi.nlm.nih.gov/36062143/
Xu WL, et al. Fratiglioni. Uncontrolled diabetes increases the risk of Alzheimer's disease: a population-based cohort study. Diabetologia. 2009;52(6): 1031-1039.
Yaffe K, et al. “Effect of Raloxifene on Prevention of Dementia and Cognitive Impairment in Older Women: The Multiple Outcomes of Raloxifene (MORE) Randomized Trial.” Am J Psychiatry. 2005 Apr;162(4):683-90.
Yamaguchi K, et al. “Stimulation of Nerve Growth Factor Production by Pyrroloquinoline Quinone and Its Derivatives in Vitro and in Vivo.” Biosci Biotechnol Biochem. 57.7 (1993): 1231-3.
Yaffe K, Vittinghoff E, Dublin S, et al. Effect of Personalized Risk-Reduction Strategies on Cognition and Dementia Risk Profile Among Older Adults: The SMARRT Randomized Clinical Trial. JAMA Intern Med. Jan 1 2024;184(1):54-62. doi:10.1001/jamainternmed.2023.6279. https://pubmed.ncbi.nlm.nih.gov/38010725/
Yang F, et al. “Curcumin Inhibits Formation of Amyloid Beta Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in Vivo.” J Biol Chem. 280.7 (2005): 5892-901.
Yang X, Wei HM, Hu GY, et al. Combining antioxidant astaxantin and cholinesterase inhibitor huperzine A boosts neuroprotection. Molecular medicine reports. 2020;21(3):1043-1050.
Yang X, et al. “Coenzyme Q10 Attenuates Beta-Amyloid Pathology in the Aged Transgenic Mice with Alzheimer Presenilin 1 Mutation.” J Mol Neurosci. 34.2 (2008): 165-71.
Yao ZX, et al. “Ginkgo biloba Extract (Egb 761) Inhibits Beta-Amyloid Production by Lowering Free Cholesterol Levels.” J Nutr Biochem. 15.12 (2004): 749-56.
Yarns BC, Holiday KA, Carlson DM, Cosgrove CK, Melrose RJ. Pathophysiology of Alzheimer's Disease. The Psychiatric clinics of North America. Dec 2022;45(4):663-676. doi:10.1016/j.psc.2022.07.003. https://pubmed.ncbi.nlm.nih.gov/36396271/
Yeh TS, Curhan GC, Yawn BP, Willett WC, Curhan SG. Herpes zoster and long-term risk of subjective cognitive decline. Alzheimers Res Ther. Aug 14 2024;16(1):180. doi:10.1186/s13195-024-01511-x. https://pubmed.ncbi.nlm.nih.gov/39138535/
Yilmaz N. “Relationship between paraoxonase and homocysteine: crossroads of oxidative diseases.” Arch Med Sci. 8.1: 138-53.
Young G, et al. “Omega-3 Fatty Acids and Neuropsychiatric Disorders.” Reprod Nutr Dev 45.1 (2005): 1-28.
Yulug B, Altay O, Li X, et al. Combined metabolic activators improve cognitive functions in Alzheimer's disease patients: a randomised, double-blinded, placebo-controlled phase-II trial. Translational neurodegeneration. Jan 26 2023;12(1):4. doi:10.1186/s40035-023-00336-2. https://pubmed.ncbi.nlm.nih.gov/36703196/
Yurko-Mauro K, et al. “Beneficial Effects of Docosahexaenoic Acid on Cognition in Age-Related Cognitive Decline.” Alzheimers Dement. 6.6 (2010): 456-64.
Zablocka A, Janusz M. Effect of the proline-rich polypeptide complex/colostrinin on the enzymatic antioxidant system. Arch Immunol Ther Exp (Warsz).Oct 2012;60(5):383-390.
Zablocka A, Ogorzalek A, Macala J, Janusz M. A proline-rich polypeptide complex (PRP) influences inducible nitric oxide synthase in mice at the protein level. Nitric oxide: biology and chemistry. Aug 01 2010;23(1):20-25.
Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: the CacheCounty Study. JAMA. 2002 Nov 6;288(17):2123-9.
Zapp LM, Slaga TJ, Zhao J. et al. Method for enhancing post-processing content of beneficial compounds in beverages naturally - United States Patent Application 20100183790. Publication Date: 2010-07-22. Available at: http://patent.ipexl.com/U2S/20100183790.html accessed 7/25/2012.
Zeng C-Y, Yang T-T, Zhou H-J, et al. Lentiviral vector–mediated overexpression of Klotho in the brain improves Alzheimer's disease–like pathology and cognitive deficits in mice. Neurobiology of Aging. 2019;78:18-28. doi:https://doi.org/10.1016/j.neurobiolaging.2019.02.003. https://pubmed.ncbi.nlm.nih.gov/30851437/
Zeng X, Ling H, Yang J, Chen J, Guo S. Proteome analysis provides insight into the regulation of bioactive metabolites in Hericium erinaceus. Gene. Aug 5 2018;666:108-115.
Zhang CC, Cao CY, Kubo M, Harada K, Yan XT, Fukuyama Y, Gao JM. Chemical Constituents from Hericium erinaceus Promote Neuronal Survival and Potentiate Neurite Outgrowth via the TrkA/Erk1/2 Pathway. International journal of molecular sciences. Jul 30 2017;18(8).
Zhang J, An S, Hu W, Teng M, Wang X, Qu Y, . . . Wang D. The Neuroprotective Properties of Hericium erinaceus in Glutamate-Damaged Differentiated PC12 Cells and an Alzheimer's Disease Mouse Model. International journal of molecular sciences. Nov 1 2016;17(11).
Zhang JJ, et al. “Protective Effect of Pyrroloquinoline Quinone against Abeta-Induced Neurotoxicity in Human Neuroblastoma SH-SY5Y Cells.” Neurosci Lett. 464.3 (2009): 165-9.
Zhang S and Yao T. [Estrogen: regulation of amyloid-beta protein metabolism and attenuation of amyloid-beta protein neurotoxicity]. Sheng Li Ke Xue Jin Zhan. 2003 Jul;34(3):197-201.
Zhang X, Heng X, Li T, et al. Long-term treatment with lithium alleviates memory deficits and reduces amyloid-beta production in an aged Alzheimer's disease transgenic mouse model. Journal of Alzheimer's disease: JAD. 2011;24(4):739-749.
Zhang XY, Zhang LH, Li CT, Chen WJ, Zhao JB, Wei EQ. [5-lipoxygenase is involved in rotenone-induced injury in PC12 cells]. Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences. Mar 2011;40(2):150-155.
Zhao L, Gong N, Liu M, et al. Beneficial synergistic effects of microdose lithium with pyrroloquinoline quinone in an Alzheimer's disease mouse model. Neurobiology of aging.Dec 2014;35(12):2736-2745.
Zhao Y, Zhao B. “Natural antioxidants in prevention and management of Alzheimer’s disease.” Front Biosci (Elite Ed). 1.4 (2012): 794-808.
Zhou P, et al. “Acetyl-L-Carnitine Attenuates Homocysteine-Induced Alzheimer-Like Histopathological and Behavioral Abnormalities.” Rejuvenation Res. 14.6 (2011): 669-79.
Zhou X, Zhang F, Hu X, Chen J, Wen X, Sun Y, . . . Song Y. Inhibition of inflammation by astaxanthin alleviates cognition deficits in diabetic mice. Physiology & behavior. Nov 01 2015;151:412-420.
Zhu Y, Prata L, Gerdes EOW, et al. Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans. EBioMedicine. Mar 2022;77:103912. doi:10.1016/j.ebiom.2022.103912. https://pubmed.ncbi.nlm.nih.gov/35292270/
Zuin M, Cherubini A, Volpato S, Ferrucci L, Zuliani G. Acetyl-cholinesterase-inhibitors slow cognitive decline and decrease overall mortality in older patients with dementia. Sci Rep. Jul 16 2022;12(1):12214. doi:10.1038/s41598-022-16476-w. https://pubmed.ncbi.nlm.nih.gov/35842477/
Wellness
Specialists
1-800-226-2370 - This service is FREE
7:30 AM - 12 AM (ET) Mon-Fri | 9 AM - 12 AM (ET) Sat-Sun
