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).

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 (AD). 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.

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).

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

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), 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).

Conventional Alzheimer’s disease treatment relies heavily upon pharmacologic modulation of cholinergic and glutamatergic neurotransmission. This can result in symptomatic improvement, though the underlying progression of the disease is unaffected. Accumulation of amyloid beta and neurofibrillary tangles are challenging to target via pharmacologic means (Pangalos 2007).

Acetylcholinesterase Inhibitors

Acetylcholinesterase inhibitors are typically first line pharmacotherapy for mild-to-moderate Alzheimer’s disease. They prevent the breakdown of acetylcholine, a chemical neurotransmitter in the brain, by inhibiting the enzyme acetylcholinesterase.

Tacrine, the first centrally-acting cholinesterase inhibitor approved by FDA for the treatment of Alzheimer's disease, was withdrawn from the U.S. market, due to possible liver toxicity (FDA 2013; Meng 2007; Mehta 2012). Cholinesterase inhibitors currently used in AD include donepezil (Aricept^®), rivastigmine (Exelon^®), and galantamine (Razadyne^®) (Uzun 2011). Although studies have repeatedly found that acetylcholinesterase inhibitors may reduce Alzheimer’s symptoms, they do not halt or reverse the underlying disease process (Gauthier 2009; Hansen 2008).

NMDA Receptor Blockers

Memantine (e.g., Namenda^®), an N-methyl-D-aspartate (NMDA) receptor antagonist (blocker), has been approved by the FDA for moderate to severe Alzheimer’s disease (Lo 2011). Although memantine may help decrease formation of NFTs, NMDA receptor antagonists have also been linked to serious adverse effects, which appear to be worsened in combination with acetylcholinesterase inhibitors (Creeley 2008).

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).

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.

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).

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).

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’ Mini-Mental Status Examination (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).

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

Multi-nutrient deficiencies have been observed in people with Alzheimer’s disease (Kristensen 1993; Jiménez-Jiménez 1997). For instance, scientists found that individuals with higher serum levels of biomarkers for vitamins B, C, D, and E, as well as for omega-3 oils most commonly found in fish (ie, EPA and DHA) were less likely to exhibit brain shrinkage or reduced cognitive function (Bowman 2011). In fact, a systematic review of 32 randomized controlled trials found that many dietary interventions, both as multi-nutrient formulations and in insolation, show potential to improve cognitive function in Alzheimer’s disease (Moreira 2020).

A study of 14 people with early-stage Alzheimer’s found that a formulation of multiple nutrients improved all measures of cognition, although the improvement in memory function was not statistically significant. The formulation comprised 680 mcg DFE (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. The cognitive improvement continued throughout the 12-month study (Chan 2008). A separate clinical study randomized 106 individuals to receive placebo or the same multi-nutrient formulation for three or six months and found the multi-nutrient formulation maintained or improved cognitive performance and mood compared with placebo (Remington 2015). In a study of 200 healthy middle-aged individuals with no cognitive or memory problems, those given a multivitamin for two months scored higher on cognitive function tests, showed less fatigue during extended cognitive challenges, achieved greater accuracy, and proved faster in mathematical processing, compared with the placebo-only group (Haskell 2010). A cross-sectional study including 4,740 respondents found that combined use of vitamin E and C supplements was associated with reduced prevalence and incidence of Alzheimer’s disease (Zandi 2004).

In a placebo-controlled study, participants with Alzheimer’s disease were randomized to receive a multi-nutrient combination or placebo for 12 months. The multi-nutrient supplement was composed of 1 gram fish oil (500 mg DHA, 150 mg EPA), 22 mg carotenoids (10 mg lutein, 10 mg meso-zeaxanthin, and 2 mg zeaxanthin), and 15 mg d-alpha tocopherol. Those given the multi-nutrient combination exhibited improved mood and memory compared with placebo (Nolan 2022). A randomized study including 69 people with Alzheimer’s analyzed the effect of a combination of metabolic activators (CMA) on cognitive function. The CMA was composed of 12.35 grams L-serine, 1 gram nicotinamide riboside, 2.55 grams NAC, and 3.73 grams L-carnitine tartrate. Patients received one dose daily of CMA or placebo for 28 days, then twice daily for an additional 56 days (total of 84 days). Patients given the CMA showed a significant improvement in cognitive functions, increased hippocampal volume and cortical thickness, and elevated plasma levels of compounds associated with NAD+ and glutathione metabolism compared with placebo (Yulug 2023).

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).