Alzheimer’s Disease

    Researchedby:
    Morgan Pfiffner

    Fact-checked

    by:

    Marina Shkayeva, Igor Deoli
    Last Updated: October 17, 2023

    Alzheimer’s disease is a neurodegenerative disorder that impairs cognitive function, especially memory formation. It is the most common type of dementia.

    examine-databaseExamine Database

    Alzheimer’s Disease falls under the Brain Health category.

    99 references on this page
    10,170 participants in 31 trials and 2 meta-analyses

    What is Alzheimer’s disease?

    Alzheimer’s disease is a form of dementia, a general term for neurological conditions that impair cognitive function to the point of interfering with daily life. It is the most common type of dementia (representing around 60 to 80% of cases) and involves a progressive degeneration of brain cells. Alzheimer’s disease is currently the fifth-leading cause of death for people older than 65 in the United States.[1]

    What do we know about the progression of Alzheimer’s disease?

    What are the main signs and symptoms of Alzheimer’s disease?

    One of the first symptoms of Alzheimer’s disease is memory loss, especially short-term memory loss of events and experiences.[8] Other common symptoms of early disease include worsening verbal memory, impaired problem solving, lack of motivation, depression, and sleep disorders. In later stages of disease, memory and cognition continue to worsen, causing disability and deterioration of motor function, in addition to significant personality changes, behavioral changes, and psychosis.

    How is Alzheimer’s disease diagnosed?

    A conclusive diagnosis of Alzheimer’s disease requires examining the brain during autopsy, meaning it can’t be definitively diagnosed in someone while they are alive. Still, doctors can make a possible or probable diagnosis based on signs and symptoms, performance on neurocognitive tests (which assess things like memory, concentration, and reasoning), and the exclusion of other causes. More recently developed diagnostic methods using ​​positron-emission tomography (PET) scans can identify amyloid accumulation (an indicator of Alzheimer’s disease) with a high level of accuracy, but this testing remains limited and is used primarily for research purposes at this time.[9]

    What are some of the main medical treatments for Alzheimer’s disease?

    No medical treatments have been clearly shown to stop or slow the underlying disease process in Alzheimer’s disease. However, some medication can improve symptoms. Acetylcholinesterase inhibitors can improve cognitive function in people with Alzheimer’s disease, although the effect is generally small.[14]

    In 2020, a medication called aducanumab was approved by the FDA for the treatment of Alzheimer’s disease based on its effects on amyloid plaques, but whether aducanumab improves clinical outcomes (e.g., cognitive function) remains to be established.[15]

    How could diet affect Alzheimer’s disease?

    A few dietary patterns are associated with a lower risk of Alzheimer’s disease. This protective relationship is perhaps most commonly found with a Mediterranean diet. Among individual components of the diet, a higher intake of saturated fat and sugar has been linked to a higher risk of Alzheimer’s disease, while a higher intake of fish has been linked to a lower risk. Unfortunately, these findings derive from observational studies, meaning cause and effect can’t be determined with certainty, and there are almost no randomized clinical trials (RCTs) looking at the effect of diet on the incidence of Alzheimer’s disease.

    Is dairy intake linked to AD risk?

    What dietary patterns are associated with a lower risk of Alzheimer’s disease?

    What foods are associated with Alzheimer’s disease?

    What effect do ketones have on Alzheimer’s disease?

    Have any supplements been studied for Alzheimer’s disease?

    RCTs have assessed a number of supplements’ effects on established Alzheimer’s disease. This includes omega-3s, B vitamins (usually folic acid, vitamin B6, and vitamin B12), vitamin D, vitamin E, ginkgo biloba, L-alpha glycerylphosphorylcholine (alpha-GPC), Lion's mane mushroom, ginseng, saffron, and sodium oligomannate. For the most part, these supplements have only conflicting or limited evidence in favor of their use.

    Is there any evidence for the use of supplements in Alzheimer’s disease?

    Are there any other treatments for Alzheimer’s disease?

    Exercise and physical activity have been shown to benefit physical function, functional independence, and neuropsychiatric symptoms in people with Alzheimer’s disease; aerobic exercise specifically improved cognitive function.

    Several trials have investigated the effect of a keto diet and ketogenic supplements (e.g., medium-chain triglycerides) on Alzheimer’s disease and observed improvements — sometimes, but not always — in quality of life and cognitive function.

    Music therapy centers around listening to music to stimulate the brain. Some research suggests the intervention can improve mood and cognitive function among people who have Alzheimer’s disease.

    What causes Alzheimer’s disease?

    The underlying cause of Alzheimer’s is not known for certain, but several explanations have been proposed. The most common theory is that Alzheimer’s disease is the result of neurodegeneration and a buildup of misfolded proteins called amyloid plaques and tau tangles, which are almost always found in the brains of people with the disease. However, this “amyloid hypothesis” has been criticized. Regardless of the cause of Alzheimer’s disease, various modifiable and nonmodifiable factors, including aging, depression, diabetes, and genetics, have been linked to a higher risk of the disease.

    What is the pathophysiology of Alzheimer’s disease?

    What are the risk factors for Alzheimer’s disease?

    Examine Database: Alzheimer’s Disease

    Panax Ginseng (Korean Ginseng)
    Ginkgo Biloba
    Phosphatidylserine
    Saffron
    Vitamin E
    Inositol
    Resveratrol
    Alpha-GPC
    Alpha-Lipoic Acid
    Bacopa Monnieri
    Curcumin
    DMAE
    Fish Oil
    Kanna
    Lion's Mane
    Oxiracetam
    Piracetam
    Vitamin D

    Research FeedRead all studies

    Frequently asked questions

    What is Alzheimer’s disease?

    Alzheimer’s disease is a form of dementia, a general term for neurological conditions that impair cognitive function to the point of interfering with daily life. It is the most common type of dementia (representing around 60 to 80% of cases) and involves a progressive degeneration of brain cells. Alzheimer’s disease is currently the fifth-leading cause of death for people older than 65 in the United States.[1]

    Alzheimer’s disease is a neurological disorder involving cognitive and functional impairments that almost always worsen with time. The disease is typically first identified by memory loss and forgetfulness, with episodic (personal experiences and events) and semantic (facts and words) memory usually impaired first. Short-term memory also becomes limited, with a smaller capacity and shorter duration. Procedural memory — how to perform functions and tasks — is not affected until much later.[2][3]

    As the disease progresses and different areas of the brain degenerate, additional symptoms develop, including mood changes, difficulty with language, trouble performing basic activities, and, in later stages, an impaired ability to swallow and breathe.

    Prior to developing Alzheimer’s disease, individuals first develop a less extreme disorder called mild cognitive impairment (MCI). Although MCI is common during older age (a time when cognitive function declines to some extent), with Alzheimer’s disease, memory problems exceed what is expected based on age. Despite MCI being a risk factor, people who develop the disorder don’t usually progress to Alzheimer’s disease[4], and there does not seem to be evidence that screening older adults for early MCI is beneficial.[5]

    Once a person is diagnosed with Alzheimer’s disease, the progression of cognitive decline is about a 3-point reduction per year on the 30-point Mini–Mental State Examination (MMSE).[6][7]

    What do we know about the progression of Alzheimer’s disease?

    In short, we don’t know as much as we would like. Genetic mutations and exposure to risk factors (e.g., cardiometabolic disorders) may slowly start to put changes into motion from birth until 40 year of age, while symptoms may not be observed until after 60 years of age. This gives a vague window from 20–60 years of age for the modification of misfolding and/or aggregation of amyloid-beta and/or tau proteins that may begin producing plaques and tangles that trigger oxidative stress and inflammation, ultimately leading to cell death and neurodegeneration. There is likely much more nuance to this process, including the influence of diet[19] and lifestyle[20] that can prevent and/or treat these characteristic modifications of AD, but more research is needed to completely understand neurodegenerative disease.

    What are the main signs and symptoms of Alzheimer’s disease?

    One of the first symptoms of Alzheimer’s disease is memory loss, especially short-term memory loss of events and experiences.[8] Other common symptoms of early disease include worsening verbal memory, impaired problem solving, lack of motivation, depression, and sleep disorders. In later stages of disease, memory and cognition continue to worsen, causing disability and deterioration of motor function, in addition to significant personality changes, behavioral changes, and psychosis.

    How is Alzheimer’s disease diagnosed?

    A conclusive diagnosis of Alzheimer’s disease requires examining the brain during autopsy, meaning it can’t be definitively diagnosed in someone while they are alive. Still, doctors can make a possible or probable diagnosis based on signs and symptoms, performance on neurocognitive tests (which assess things like memory, concentration, and reasoning), and the exclusion of other causes. More recently developed diagnostic methods using ​​positron-emission tomography (PET) scans can identify amyloid accumulation (an indicator of Alzheimer’s disease) with a high level of accuracy, but this testing remains limited and is used primarily for research purposes at this time.[9]

    All forms of dementia — Alzheimer’s disease included — share overarching diagnostic criteria. According to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), a diagnosis of dementia (which they classify as a “major neurocognitive disorder”) requires meeting the following criteria (using a person’s medical history and cognitive assessment):

    • An impairment in one or more cognitive domains (e.g., executive function, language, memory.)

    • A decline in cognitive ability compared with past levels of functioning

    • An impairment in the ability to function independently in daily life

    • Symptoms not occurring as a result of delirium

    In addition to a dementia diagnosis, conclusively determining whether a person has Alzheimer’s disease requires an autopsy to see if amyloid plaques are present in the brain. This limits diagnosis to after death, which is not ideal. To help diagnose a person while still alive, other types of dementia can be ruled out, thereby increasing the likelihood that Alzheimer’s disease is present. As a result, Alzheimer’s has been referred to as a “disease of exclusion”.

    Some other common types of dementia are Lewy body dementia, vascular dementia, and frontotemporal (frontal and temporal lobe) dementia. In general, they vary somewhat in their presentation.

    Common types of dementia

    TypePathologyPercentage of all dementiaCharacteristics
    Alzheimer’s diseaseAmyloid plaques and neurofibrillary tangles in the brain60–80%Gradual onset, Progressive course, Multiple cognitive deficits, including memory impairment
    Vascular dementiaMarker of cardiovascular disease (CVD) event (stroke, blockage in arteries)20%Abrupt onset, fluctuating course, history of CVD event, focal deficits (abnormal gait, muscle weakness, etc.)
    Lewy body dementiaAlpha-synuclein aggregates in the brain5–15%Fluctuations in cognition, hallucinations, difficulty walking
    Frontotemporal dementiaDegeneration of frontal and temporal lobes3% (people >65 years old) and 10% (people <65 years old)Difficulty with language (aphasia), executive dysfunction, visuospatial function usually unaffected
    Adapted from Duong, et al. Can Pharm J(Ott). 2017 Feb[10] and Hogan, et al. Can J Neurol Sci. 2016 Apr[11]

    Finally, because Alzheimer’s disease nearly universally features a buildup of amyloid plaques (covered in more detail in the next section), PET scans can be used to differentiate Alzheimer’s disease from other dementia types.[13] Typical radiolabeled compounds are infused into a person’s bloodstream to run these tests. Following infusion, these compounds will make their way into the brain. They have a high affinity for amyloid, meaning the compounds will temporarily accumulate in the brain if more amyloid is present or flow out of the brain if little amyloid is present. When the brain is then imaged using a PET scan, the compounds are visible and serve as a proxy for how much amyloid is present, allowing for a more conclusive diagnosis of Alzheimer’s disease. The use of these PET scans is not widespread, though, due in part to the limited clinical utility (definitive Alzheimer’s diagnosis doesn’t typically alter the treatment plan).

    What are some of the main medical treatments for Alzheimer’s disease?

    No medical treatments have been clearly shown to stop or slow the underlying disease process in Alzheimer’s disease. However, some medication can improve symptoms. Acetylcholinesterase inhibitors can improve cognitive function in people with Alzheimer’s disease, although the effect is generally small.[14]

    In 2020, a medication called aducanumab was approved by the FDA for the treatment of Alzheimer’s disease based on its effects on amyloid plaques, but whether aducanumab improves clinical outcomes (e.g., cognitive function) remains to be established.[15]

    How could diet affect Alzheimer’s disease?

    A few dietary patterns are associated with a lower risk of Alzheimer’s disease. This protective relationship is perhaps most commonly found with a Mediterranean diet. Among individual components of the diet, a higher intake of saturated fat and sugar has been linked to a higher risk of Alzheimer’s disease, while a higher intake of fish has been linked to a lower risk. Unfortunately, these findings derive from observational studies, meaning cause and effect can’t be determined with certainty, and there are almost no randomized clinical trials (RCTs) looking at the effect of diet on the incidence of Alzheimer’s disease.

    Is dairy intake linked to AD risk?

    In a cohort study[16] of 37,689 participants from the U.S. Women’s Health Initiative — Dietary Modification Trial (WHI-DM), lactose was the only sugar out of six subtypes that was significantly associated with AD risk. This suggests that dairy intake may increase AD risk, but other studies have found the opposite[17] or no effect[18].

    What dietary patterns are associated with a lower risk of Alzheimer’s disease?

    Several dietary patterns and foods have been associated with a lower risk of Alzheimer’s disease. Currently, this evidence is entirely observational, as no clinical trials have assessed the effect of dietary patterns or foods (supplements excluded) on Alzheimer’s disease risk.

    Mediterranean-style diets

    Mediterranean-style diets are characterized by a higher intake of fish, fruits and vegetables, legumes, nuts, whole grains, and olive oil; limited intake of meat and dairy; and moderate intake of alcohol (often wine specifically).

    A 2021 systematic review and meta-analysis found observational evidence that adherence to a Mediterranean diet was associated with lower risks of both mild cognitive impairment and Alzheimer’s disease.[66]

    MIND diet

    The MIND (​​Mediterranean-DASH Intervention for Neurodegenerative Delay) diet incorporates elements of the Mediterranean-style and DASH (Dietary Approaches to Stop Hypertension) diets. It favors berries, beans, vegetables, leafy greens, whole grains, and olive oil; includes moderate fish, poultry, and wine (one glass per day); and limits sweets, cheese, butter, red meat, and fried foods. The MIND diet has been the subject of less research than the Mediterranean diet, but at least one cohort study found that higher adherence to the MIND diet was associated with a lower risk of Alzheimer’s disease.[67]

    Ketogenic diet

    A ketogenic diet shows some evidence of benefit for people with Alzheimer’s disease, which is covered in more detail in a later section. There is currently no evidence that a ketogenic diet can prevent Alzheimer’s disease.

    What foods are associated with Alzheimer’s disease?

    Sugar

    A prospective cohort study published in 2021 found that a higher intake of sugar-containing beverages was associated with a higher risk of Alzheimer’s disease.[68] Similarly, a 2021 study covered here found that a diet high in sugar was associated with greater amyloid accumulation in two areas of the brain: the posterior cingulate gyrus and precuneus.

    Fish

    Fish Intake has been associated with a lower risk of Alzheimer’s disease. A 2014 meta-analysis of six prospective cohort studies found that a 100-gram increase in weekly fish intake was associated with an 11% lower risk of Alzheimer’s disease.[69] A 2018 meta-analysis of five prospective cohort studies likewise found an association between higher fish intake and a lower risk of Alzheimer’s disease among people with a genetic predisposition to the disease.[70]

    Although a possible candidate for this protective association are the omega-3 fatty acids found in seafood, this does not appear to be the case. In the 2014 meta-analysis, a higher intake of long-chain omega-3s was not associated with a lower Alzheimer’s disease.

    Coffee

    A 2018 meta-analysis of five prospective cohort studies found no association between coffee consumption of up to 5 cups per day and risk of Alzheimer’s disease.[71] However, at least one study found that drinking more than six cups of coffee per day was associated with a higher risk of Alzheimer’s disease.[72] It’s worth noting that disturbed sleep appears to increase brain levels of amyloid beta,[64] and a 2017 meta-analysis found that having sleep problems was associated with a higher risk of Alzheimer’s disease.[65] Given that caffeine is one factor that can negatively impact sleep, being mindful of caffeine intake (from coffee and other sources) may be important in reducing Alzheimer’s risk.

    Alcohol

    Observational evidence has frequently found that light-to-moderate alcohol consumption is associated with a lower risk of Alzheimer’s disease compared with no alcohol consumption.[73][74] One concern raised with this data, however, is that these findings could be the result of confounding factors (e.g., people who drink in moderation may be more likely to have other healthy habits).[75] This would also explain why genetic evidence largely hasn’t found a beneficial link between alcohol and Alzheimer’s disease.[76][74]

    Meanwhile, one study, utilizing data from seven cohort studies, found that a history of drinking to the point of losing consciousness (i.e., passing out) was associated with roughly double the risk of Alzheimer’s disease.[77]

    What effect do ketones have on Alzheimer’s disease?

    Alzheimer’s disease commonly features a reduced ability to generate energy from glucose, and this deficit may largely affect cognitive function. So how might this be remedied? Enter ketones. Some evidence suggests that although glucose metabolism may be impaired, the brain’s ability to utilize ketone bodies for energy is relatively unaffected, at least in the early stages of Alzheimer’s disease.[97] Given this, a ketogenic diet or ketogenic supplements may improve neuronal energy production and produce clinical benefits.

    One RCT looked at the effect of a ketogenic supplement called AC-1202 (which consists mostly of caprylic acid) on cognitive function among 152 people with mild to moderate Alzheimer’s disease.[98] For 90 days participants took either AC-1202 or a placebo, with cognitive function assessed using two tests: the ADAS-Cog and MMSE. ADAS-Cog scores had improved at day 45, but not at day 90, and there was no difference in MMSE scores between groups at any point. Interestingly, a subgroup analysis found that ADAS-Cog scores were improved at days 45 and 90 in non-carriers of APOE4 but not improved at either time point in carriers of the gene.

    A crossover RCT published in 2021 examined the effect of a ketogenic diet on 26 people with Alzheimer’s disease.[99] Participants were assigned to follow either a ketogenic diet (with a target of 6% of calories from carbohydrates) or low-fat diet for 12 weeks, later switching to the other diet after a 10-week washout period. Compared with the low-fat diet, the ketogenic diet improved both the ability to perform daily activities and quality of life. The ketogenic diet did not improve cognitive function in the overall analysis, but an improvement was seen when compliance was factored in (including only assessing participants who achieved a beta-hydroxybutyrate (a ketone body) level of at least 0.6 millimoles per liter).

    Have any supplements been studied for Alzheimer’s disease?

    RCTs have assessed a number of supplements’ effects on established Alzheimer’s disease. This includes omega-3s, B vitamins (usually folic acid, vitamin B6, and vitamin B12), vitamin D, vitamin E, ginkgo biloba, L-alpha glycerylphosphorylcholine (alpha-GPC), Lion's mane mushroom, ginseng, saffron, and sodium oligomannate. For the most part, these supplements have only conflicting or limited evidence in favor of their use.

    Is there any evidence for the use of supplements in Alzheimer’s disease?

    B vitamins

    High levels of the amino acid homocysteine have been associated with a higher risk of Alzheimer’s disease.[78] Because folic-acid, vitamin-b6, and vitamin-b12 play a central role in the metabolism of homocysteine, these vitamins have been extensively tested in clinical trials for their ability to improve cognitive function after the onset of Alzheimer’s disease, with the evidence as a whole indicating little-to-no benefit.

    Vitamin D

    A large body of evidence suggests the immune system facilitates Alzheimer’s disease.[79] Given this, vitamin D, which can influence immune function, may have an effect on the disease. One clinical trial supports a beneficial effect of vitamin D supplementation in people with Alzheimer’s disease. Mendelian randomization trials have also found that having genetically higher vitamin D levels seems to lower the risk of developing Alzheimer’s disease.[80][81]

    Vitamin E

    Oxidative stress, including oxidative damage to neuronal proteins and DNA, seems to occur during the development of Alzheimer’s disease.[82][83] If this process contributes to the development and progression of Alzheimer’s disease, a viable intervention could be supplementing with vitamin E, a potent antioxidant. A few clinical trials have tested the effect of a very high dose of vitamin E on people with Alzheimer’s disease, with some mixed evidence of benefit, but vitamin E supplementation does not seem to prevent dementia or Alzheimer’s disease in at-risk people.

    Omega-3 fatty acids

    The human brain contains a large quantity of the LCn3 docosahexaenoic acid (DHA),[84] making it a reasonable hypothesis that supplementing with DHA and its precursor, eicosapentaenoic acid (EPA), could benefit brain health. Additionally, experiments on rodent models of Alzheimer’s disease have provided support for a beneficial effect of LCn3s.[85][86] Despite this, clinical trials looking at the effect of LCn3s among people with Alzheimer’s disease suggest no benefit. More research is needed to determine whether supplementation with omega-3 fatty acids can help prevent Alzheimer’s disease.

    Alpha-GPC

    Acetylcholine is a neurotransmitter involved in cognitive function, and reductions in its signaling contribute to some of the symptoms of Alzheimer’s disease. As a result, people with the disease are frequently prescribed medications called acetylcholinesterase inhibitors (AChEIs), which inhibit the breakdown of acetylcholine, thereby increasing its levels in synapses. AChEIs can modestly benefit symptoms of Alzheimer’s disease but do not slow progression of the disease itself.[87]

    L-Alpha glycerylphosphorylcholine, or alpha-GPC, is a choline-containing compound that is believed to better deliver choline to the brain, where it can be used for acetylcholine synthesis (acetylcholine is made from choline and a molecule called acetyl-CoA). Preliminary evidence from a few clinical trials suggests alpha-GPC is beneficial for people with Alzheimer’s disease.

    Ginkgo biloba

    Ginkgo biloba tree leaves, commonly known simply as ginkgo biloba, are often used as a dietary supplement and contain a variety of terpenoids (a type of plant metabolite) known as ginkgolides. Ginkgo biloba may increase cerebral blood flow,[88] which could benefit brain health, and ginkgolides have shown some benefit in animal models of Alzheimer’s disease.[89] Although several clinical trials indicate ginkgo biloba may be beneficial for Alzheimer’s, the data as a whole are somewhat inconsistent (with seemingly variable responses based on the test used) and often have serious shortcomings (e.g., poor distinction between Alzheimer’s disease and other dementia types). Ginkgo biloba does not seem to prevent Alzheimer’s disease.

    Lion’s mane mushroom

    It has been posited that Hericium erinaceus, commonly known as lion’s mane mushroom, benefits cognitive function, partly based on research suggesting it increases levels of nerve growth factor (NGF), a peptide important to the growth and survival of neurons. However, whether lion’s mane (or, more specifically, terpenoids called erinacines, found in lion’s mane) actually stimulates NGF remains a source of debate. Highly preliminary research from a few clinical trials indicates lion’s mane may be beneficial for people with or at risk of Alzheimer’s disease.

    Panax ginseng

    Panax ginseng (aka Asian ginseng, Chinese ginseng, Korean ginseng, or even just ginseng) is a plant whose roots are often used as a supplement. One component of panax ginseng, called gintonin, has been studied in animal models for its potential to inhibit amyloid beta toxicity[90][91], making it a possible candidate for improving — or at least slowing — cognitive decline due to Alzheimer’s disease. Preliminary evidence from a few clinical trials suggests panax ginseng is beneficial for people with the disease.

    Saffron

    Saffron contains potentially bioactive compounds, including crocin, crocetin, and safranal, that experiments performed in rodent models suggest may be able to reduce the accumulation and toxicity of amyloid beta.[92][93][94][95] Preliminary evidence from a few clinical trials suggests saffron is beneficial for Alzheimer’s disease.

    Sodium oligomannate

    Sodium oligomannate is a supplement (sold as GV-971) made from oligosaccharides (sugars) in a species of kelp called Ecklonia kurome. Some research suggests sodium oligomannate may reduce amyloid beta deposits in the brain (possibly via effects on the microbiome),[96] and one trial by a company that sells a sodium oligomannate supplement found that it benefited cognition in people with Alzheimer’s disease.

    Are there any other treatments for Alzheimer’s disease?

    Exercise and physical activity have been shown to benefit physical function, functional independence, and neuropsychiatric symptoms in people with Alzheimer’s disease; aerobic exercise specifically improved cognitive function.

    Several trials have investigated the effect of a keto diet and ketogenic supplements (e.g., medium-chain triglycerides) on Alzheimer’s disease and observed improvements — sometimes, but not always — in quality of life and cognitive function.

    Music therapy centers around listening to music to stimulate the brain. Some research suggests the intervention can improve mood and cognitive function among people who have Alzheimer’s disease.

    What causes Alzheimer’s disease?

    The underlying cause of Alzheimer’s is not known for certain, but several explanations have been proposed. The most common theory is that Alzheimer’s disease is the result of neurodegeneration and a buildup of misfolded proteins called amyloid plaques and tau tangles, which are almost always found in the brains of people with the disease. However, this “amyloid hypothesis” has been criticized. Regardless of the cause of Alzheimer’s disease, various modifiable and nonmodifiable factors, including aging, depression, diabetes, and genetics, have been linked to a higher risk of the disease.

    What is the pathophysiology of Alzheimer’s disease?

    The underlying cause of Alzheimer’s disease is far from a settled subject, but examining shared brain characteristics of people with the disease may provide insights.

    One of the main features of Alzheimer’s disease is the accumulation in the brain of amyloid plaques,[21] which are made of a peptide called amyloid beta and have been proposed as a major driver of Alzheimer’s disease. This “amyloid hypothesis” has been challenged,[22] however, notably because drugs targeting the amyloid pathway have not improved cognition in Alzheimer’s disease.[23]

    Another primary feature of Alzheimer’s disease is the presence of neurofibrillary tangles,[24] which are made up of tau proteins that, like amyloid beta, have misfolded and aggregated in the brain. According to the “tau hypothesis”, these tangles are a cause of or contributor to Alzheimer’s disease. However, because tau proteins serve important functions in the brain, another possibility is that the tangles are simply an indicator of a loss of tau function and are not harmful themselves.

    Also common in Alzheimer’s disease is glucose hypometabolism,[25] a reduction in the brain’s ability to use glucose (a type of sugar) for energy, which is why some researchers call Alzheimer’s “type 3 diabetes”.[26] This reduction in the brain’s energy production may contribute to the cognitive impairments seen with Alzheimer’s disease and to the development of the disease itself.[27]

    Finally, Alzheimer’s disease is neurodegenerative: it is characterized by the death of neurons (a type of brain cell) and subsequent cerebral atrophy (shrinking of the brain).[28] This process is believed to be central to the disease process and may be the result, at lea

    What are the risk factors for Alzheimer’s disease?

    Aging

    One of the most important risk factors for Alzheimer’s disease is older age. The prevalence of Alzheimer’s disease is around 3% between ages 65 and 74, increases to 17% between 75 and 84, and reaches 32% at 85 or older.[29]

    Depression

    Depression has long been linked to the disease, with a 2021 meta-analysis of 28 prospective cohort studies reporting that the presence of depression or depression symptoms was associated with a 54% higher risk of Alzheimer’s disease.[30] Additionally, many genes that increase Alzheimer’s disease risk seem to do so by increasing the risk of depression.[31]

    Being female

    The overall incidence of Alzheimer’s disease is higher among females than males.[32] A major reason for this could simply be that women live longer than men and, as previously noted, risk increases with age.[33] Another contributing factor could be depression, which occurs more often in women[34] and, as covered, is associated with a higher risk of Alzheimer’s disease. Among females, the use of estrogen replacement therapy is associated with a lower risk of Alzheimer’s, but this has not been confirmed in clinical trials.[35]

    Head injuries

    Head injuries, such as a traumatic brain injury (TBI), may increase the risk of neurodegenerative disorders. Evidence suggests people who have experienced a TBI have higher odds of developing dementia,[36] but the evidence is somewhat mixed as to whether TBIs increase the risk of Alzheimer’s disease specifically.[37][38] It’s possible that characteristics of the injury itself could determine its effect on Alzheimer’s risk, but more research is needed.

    Limited cognitive reserve

    Some people seem capable of experiencing a significant amount of the neuronal death and amyloid plaque accumulation that characterize Alzheimer’s disease without displaying cognitive symptoms of the disease itself.[39][40] A major hypothesis used to explain these unusual cases is cognitive reserve.

    Cognitive reserve refers to the capacity of the brain to compensate for damage and maintain function, and is believed to vary from person to person. The greater a person’s cognitive reserve, the longer it is believed to take for the underlying brain changes to induce cognitive impairment. In line with this, the risk of Alzheimer’s disease is lower in people with higher levels of education,[41] a factor believed to increase cognitive reserve.

    Another related concept, neuroplasticity, is a broad term for the brain’s ability to alter itself. This can involve rerouting neural pathways, in some cases as a way of replacing damaged ones. An extreme example of this was described in a case study of a 29-year-old woman who had a significant stroke that required the removal of the right hemisphere of her brain.[42] This initially resulted in impairments in aspects of her cognitive function, including visuospatial ability, organization, and problem solving, but when examined around 5 years later, her cognitive function appeared to be normal, likely due in part to neuroplasticity.

    Some factors that may promote neuroplasticity are adequate sleep, physical activity, and environmental enrichment.[43]

    Limited physical activity

    A large number of prospective cohort studies have found that physical activity is associated with a lower risk of Alzheimer’s disease.[44][44] In one meta-analysis of prospective cohort studies, compared with little or no physical activity, high amounts of physical activity was associated with a 38% lower risk of Alzheimer’s disease and moderate amounts, with a 29% lower risk.

    Diabetes

    Type 2 diabetes has frequently been associated with a higher risk of Alzheimer’s disease, with two meta-analyses finding an increase of about 55 to 57%.[45][46] A number of mechanisms have been suggested to explain this finding, but confirmation has remained elusive. One theory is that the brain becomes insulin resistant, and the resulting reduction in neuronal insulin signaling increases the production of amyloid beta, the main component of amyloid plaques.[47]

    Of note, the relationship between diabetes and Alzheimer’s disease does not seem to be explained by differences in body weight, as the association remains after adjusting for body mass index(BMI).[45]

    Some evidence suggests people with type 1 diabetes may also be at higher risk of developing dementia.[48][49] These studies did not differentiate dementia type, however, meaning more research is needed to determine whether type 1 diabetes is associated with a higher risk of Alzheimer’s disease or a different form of dementia (e.g., vascular dementia).

    Elevated body weight

    A 2020 meta-analysis of prospective cohort studies found that being overweight or obese at midlife was associated with a higher risk of Alzheimer’s disease.[50] One possible explanation could be that elevated body fat promotes greater insulin resistance and a higher risk of type 2 diabetes, a risk factor for Alzheimer’s disease, as discussed. Interestingly, the prior meta-analysis also found being overweight (and, in high-quality studies, obese) during later life was associated with a lower risk of Alzheimer’s disease. It’s possible this merely reflects reverse confounding, as some research suggests people begin to lose weight in the years leading up to their dementia diagnosis.[51]

    Abnormal blood pressure

    Meta-analyses of numerous prospective cohort studies have found that hypertension (high blood pressure) around midlife (ages 45 to 65) is associated with a higher risk of Alzheimer’s disease.[52][41] Hypertension was not found to be associated with Alzheimer’s disease in later life (≥65 years old), although in one meta-analysis, use of antihypertensive medication during this time was nonetheless associated with a lower risk.[52]

    Several abnormal blood pressure patterns have also been associated with a higher risk of Alzheimer’s disease, including orthostatic hypotension (low blood pressure when rising from a sitting position);[41] higher blood pressure in the evening, relative to the daytime;[53] and increased fluctuations in blood pressure (i.e., throughout the day or from day to day).[54]

    Microbes in the brain

    A growing body of evidence suggests amyloid beta may function as an antimicrobial peptide, binding to bacteria and viruses and preventing infection and disease.[55]

    The herpes virus (typically herpes simplex virus 1; HSV-1) is present more often in the brains of people with Alzheimer’s than those without the disease.[56] This has led to the theory that amyloid beta is produced as a protective response to the herpes virus in the brain and inadvertently promotes Alzheimer’s disease.[57]

    Another microbe linked to Alzheimer’s disease, Porphyromonas gingivalis, is also associated with periodontal disease, which itself is linked to Alzheimer’s disease.[58] Compounds called gingipains, produced by this bacteria, have been observed at higher rates in the brains of people with Alzheimer’s disease and these gingipains have been shown to produce neurotoxic effects in mice.[59]

    Poor sleep quality

    The glymphatic system is a sort of biological drainage system that moves fluid into and out of the brain. This fluid has been shown to collect amyloid beta and clear some of it from the brain,[60] and the rate of this clearance increases dramatically during sleep.[61] As a result, it’s been theorized that inadequate sleep may promote Alzheimer’s disease by disrupting the removal of amyloid beta. However, the evidence for this hypothesis is mixed.

    By and large, prospective cohort studies have not found an association between shorter sleep duration (about 6 hours or fewer per night) and a higher risk of Alzheimer’s disease, but they have found a higher risk with longer sleep duration (around 9 or more hours per night).[62] Most of these studies relied on self-reported sleep times, however, and several studies have found that people often inaccurately assess how much they sleep.[63]

    Meanwhile, a number of observational studies have found that poor sleep quality is associated with a higher risk of Alzheimer’s disease, including when using objective measures of sleep efficiency (e.g., wrist actigraph, which records movement through a device worn on the wrist).[64][65] Still, it’s important to note that neurodegenerative diseases can disrupt areas of the brain involved in sleep regulation, meaning it’s possible that poor sleep could simply be a consequence of early brain changes in the years leading up to a dementia diagnosis.

    Update History

    Citations added

    minor

    Reviewed by

    Expert review complete

    minor

    Reviewed by

    References

    1. ^2021 Alzheimer's disease facts and figures.Alzheimers Dement.(2021 Mar)
    2. ^Jahn HMemory loss in Alzheimer's disease.Dialogues Clin Neurosci.(2013-Dec)
    3. ^Mortamais M, Ash JA, Harrison J, Kaye J, Kramer J, Randolph C, Pose C, Albala B, Ropacki M, Ritchie CW, Ritchie KDetecting cognitive changes in preclinical Alzheimer's disease: A review of its feasibility.Alzheimers Dement.(2017-Apr)
    4. ^Mitchell AJ, Shiri-Feshki MRate of progression of mild cognitive impairment to dementia--meta-analysis of 41 robust inception cohort studies.Acta Psychiatr Scand.(2009-Apr)
    5. ^Carrie D. Patnode, Leslie A. Perdue, Rebecca C. Rossom, Megan C. Rushkin, Nadia Redmond, Rachel G. Thomas, Jennifer S. LinScreening for Cognitive Impairment in Older Adults: An Evidence Update for the U.S. Preventive Services Task Force Internet
    6. ^Han L, Cole M, Bellavance F, McCusker J, Primeau FTracking cognitive decline in Alzheimer's disease using the mini-mental state examination: a meta-analysis.Int Psychogeriatr.(2000-Jun)
    7. ^Clark CM, Sheppard L, Fillenbaum GG, Galasko D, Morris JC, Koss E, Mohs R, Heyman AVariability in annual Mini-Mental State Examination score in patients with probable Alzheimer disease: a clinical perspective of data from the Consortium to Establish a Registry for Alzheimer's Disease.Arch Neurol.(1999-Jul)
    8. ^Kumar A, Sidhu J, Goyal A, Tsao JWAlzheimer DiseaseStatPearls.(2022-06)
    9. ^Weller J, Budson ACurrent understanding of Alzheimer's disease diagnosis and treatment.F1000Res.(2018)
    10. ^Silvia Duong, Tejal Patel, Feng ChangDementia: What pharmacists need to knowCan Pharm J (Ott).(2017 Feb 7)
    11. ^David B Hogan, Nathalie Jetté, Kirsten M Fiest, Jodie I Roberts, Dawn Pearson, Eric E Smith, Pamela Roach, Andrew Kirk, Tamara Pringsheim, Colleen J MaxwellThe Prevalence and Incidence of Frontotemporal Dementia: a Systematic ReviewCan J Neurol Sci.(2016 Apr)
    12. ^Tripathi M, Vibha DReversible dementias.Indian J Psychiatry.(2009-Jan)
    13. ^Schilling LP, Zimmer ER, Shin M, Leuzy A, Pascoal TA, Benedet AL, Borelli WV, Palmini A, Gauthier S, Rosa-Neto PImaging Alzheimer's disease pathophysiology with PET.Dement Neuropsychol.(2016)
    14. ^Marucci G, Buccioni M, Ben DD, Lambertucci C, Volpini R, Amenta FEfficacy of acetylcholinesterase inhibitors in Alzheimer's disease.Neuropharmacology.(2021-06-01)
    15. ^Tampi RR, Forester BP, Agronin MAducanumab: evidence from clinical trial data and controversies.Drugs Context.(2021)
    16. ^Longjian Liu, Stella L Volpe, Jennifer A Ross, Jessica A Grimm, Elisabeth J Van Bockstaele, Howard J EisenDietary sugar intake and risk of Alzheimer's disease in older womenNutr Neurosci.(2021 Jul 30)
    17. ^Mio Ozawa, Tomoyuki Ohara, Toshiharu Ninomiya, Jun Hata, Daigo Yoshida, Naoko Mukai, Masaharu Nagata, Kazuhiro Uchida, Tomoko Shirota, Takanari Kitazono, Yutaka KiyoharaMilk and dairy consumption and risk of dementia in an elderly Japanese population: the Hisayama StudyJ Am Geriatr Soc.(2014 Jul)
    18. ^Jounghee Lee, Zhuxuan Fu, Mei Chung, Dai-Ja Jang, Hae-Jeung LeeRole of milk and dairy intake in cognitive function in older adults: a systematic review and meta-analysisNutr J.(2018 Aug 27)
    19. ^Claire T McEvoy, Yue Leng, Geeske Mee Peeters, Allison R Kaup, Isabel E Allen, Kristine YaffeInterventions involving a major dietary component improve cognitive function in cognitively healthy adults: a systematic review and meta-analysisNutr Res.(2019 Jun)
    20. ^Klodian Dhana, Denis A Evans, Kumar B Rajan, David A Bennett, Martha C MorrisHealthy lifestyle and the risk of Alzheimer dementia: Findings from 2 longitudinal studiesNeurology.(2020 Jul 28)
    21. ^M Paul Murphy, Harry LeVine 3rdAlzheimer's disease and the amyloid-beta peptideJ Alzheimers Dis.(2010)
    22. ^Michael A Castello, Salvador SorianoOn the origin of Alzheimer's disease. Trials and tribulations of the amyloid hypothesisAgeing Res Rev.(2014 Jan)
    23. ^Li-Kai Huang, Shu-Ping Chao, Chaur-Jong HuClinical trials of new drugs for Alzheimer diseaseJ Biomed Sci.(2020 Jan 6)
    24. ^Athanasios Metaxas, Stefan J KempfNeurofibrillary tangles in Alzheimer's disease: elucidation of the molecular mechanism by immunohistochemistry and tau protein phospho-proteomicsNeural Regen Res.(2016 Oct)
    25. ^Lisa Mosconi, Alberto Pupi, Mony J De LeonBrain glucose hypometabolism and oxidative stress in preclinical Alzheimer's diseaseAnn N Y Acad Sci.(2008 Dec)
    26. ^Suzanne M de la Monte, Jack R WandsAlzheimer's disease is type 3 diabetes-evidence reviewedJ Diabetes Sci Technol.(2008 Nov)
    27. ^Yuri Zilberter, Misha ZilberterThe vicious circle of hypometabolism in neurodegenerative diseases: Ways and mechanisms of metabolic correctionJ Neurosci Res.(2017 Nov)
    28. ^Takako Niikura, Hirohisa Tajima, Yoshiko KitaNeuronal cell death in Alzheimer's disease and a neuroprotective factor, humaninCurr Neuropharmacol.(2006 Apr)
    29. ^2020 Alzheimer's disease facts and figures.Alzheimers Dement.(2020 Mar 10)
    30. ^Sáiz-Vázquez O, Gracia-García P, Ubillos-Landa S, Puente-Martínez A, Casado-Yusta S, Olaya B, Santabárbara JDepression as a Risk Factor for Alzheimer's Disease: A Systematic Review of Longitudinal Meta-Analyses.J Clin Med.(2021-Apr-21)
    31. ^Harerimana NV, Liu Y, Gerasimov ES, Duong D, Beach TG, Reiman EM, Schneider JA, Boyle P, Lori A, Bennett DA, Lah JJ, Levey AI, Seyfried NT, Wingo TS, Wingo APGenetic Evidence Supporting a Causal Role of Depression in Alzheimer's Disease.Biol Psychiatry.(2022-07-01)
    32. ^S Seshadri, P A Wolf, A Beiser, R Au, K McNulty, R White, R B D'AgostinoLifetime risk of dementia and Alzheimer's disease. The impact of mortality on risk estimates in the Framingham StudyNeurology.(1997 Dec)
    33. ^Beam CR, Kaneshiro C, Jang JY, Reynolds CA, Pedersen NL, Gatz MDifferences Between Women and Men in Incidence Rates of Dementia and Alzheimer's Disease.J Alzheimers Dis.(2018)
    34. ^Salk RH, Hyde JS, Abramson LYGender differences in depression in representative national samples: Meta-analyses of diagnoses and symptoms.Psychol Bull.(2017-Aug)
    35. ^Song YJ, Li SR, Li XW, Chen X, Wei ZX, Liu QS, Cheng YThe Effect of Estrogen Replacement Therapy on Alzheimer's Disease and Parkinson's Disease in Postmenopausal Women: A Meta-Analysis.Front Neurosci.(2020)
    36. ^Snowden TM, Hinde AK, Reid HMO, Christie BRDoes Mild Traumatic Brain Injury Increase the Risk for Dementia? A Systematic Review and Meta-Analysis.J Alzheimers Dis.(2020)
    37. ^Gu D, Ou S, Liu GTraumatic Brain Injury and Risk of Dementia and Alzheimer's Disease: A Systematic Review and Meta-Analysis.Neuroepidemiology.(2022)
    38. ^Li Y, Li Y, Li X, Zhang S, Zhao J, Zhu X, Tian GHead Injury as a Risk Factor for Dementia and Alzheimer's Disease: A Systematic Review and Meta-Analysis of 32 Observational Studies.PLoS One.(2017)
    39. ^Stern YWhat is cognitive reserve? Theory and research application of the reserve concept.J Int Neuropsychol Soc.(2002-Mar)
    40. ^Stern YCognitive reserve.Neuropsychologia.(2009-Aug)
    41. ^Jin-Tai Yu, Wei Xu, Chen-Chen Tan, Sandrine Andrieu, John Suckling, Evangelos Evangelou, An Pan, Can Zhang, Jianping Jia, Lei Feng, Ee-Heok Kua, Yan-Jiang Wang, Hui-Fu Wang, Meng-Shan Tan, Jie-Qiong Li, Xiao-He Hou, Yu Wan, Lin Tan, Vincent Mok, Lan Tan, Qiang Dong, Jacques Touchon, Serge Gauthier, Paul S Aisen, Bruno VellasEvidence-based prevention of Alzheimer's disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trialsJ Neurol Neurosurg Psychiatry.(2020 Jul 20)
    42. ^Bowren M, Tranel D, Boes ADPreserved Cognition After Right Hemispherectomy.Neurol Clin Pract.(2021-Dec)
    43. ^Mandolesi L, Gelfo F, Serra L, Montuori S, Polverino A, Curcio G, Sorrentino GEnvironmental Factors Promoting Neural Plasticity: Insights from Animal and Human Studies.Neural Plast.(2017)
    44. ^Guure CB, Ibrahim NA, Adam MB, Said SMImpact of Physical Activity on Cognitive Decline, Dementia, and Its Subtypes: Meta-Analysis of Prospective Studies.Biomed Res Int.(2017)
    45. ^Gudala K, Bansal D, Schifano F, Bhansali ADiabetes mellitus and risk of dementia: A meta-analysis of prospective observational studies.J Diabetes Investig.(2013-Nov-27)
    46. ^Vagelatos NT, Eslick GDType 2 diabetes as a risk factor for Alzheimer's disease: the confounders, interactions, and neuropathology associated with this relationship.Epidemiol Rev.(2013)
    47. ^Li X, Song D, Leng SXLink between type 2 diabetes and Alzheimer's disease: from epidemiology to mechanism and treatment.Clin Interv Aging.(2015)
    48. ^Kuo CL, Lu CL, Chang YH, Li CYPopulation-Based Cohort Study on Dementia Risk in Patients with Type 1 Diabetes Mellitus.Neuroepidemiology.(2018)
    49. ^Gilsanz P, Schnaider Beeri M, Karter AJ, Quesenberry CP, Adams AS, Whitmer RADepression in type 1 diabetes and risk of dementia.Aging Ment Health.(2019-07)
    50. ^Yi Qu, He-Ying Hu, Ya-Nan Ou, Xue-Ning Shen, Wei Xu, Zuo-Teng Wang, Qiang Dong, Lan Tan, Jin-Tai YuAssociation of body mass index with risk of cognitive impairment and dementia: A systematic review and meta-analysis of prospective studiesNeurosci Biobehav Rev.(2020 Aug)
    51. ^Singh-Manoux A, Dugravot A, Shipley M, Brunner EJ, Elbaz A, Sabia S, Kivimaki MObesity trajectories and risk of dementia: 28 years of follow-up in the Whitehall II Study.Alzheimers Dement.(2018-02)
    52. ^Ou YN, Tan CC, Shen XN, Xu W, Hou XH, Dong Q, Tan L, Yu JTBlood Pressure and Risks of Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of 209 Prospective Studies.Hypertension.(2020-07)
    53. ^Tan X, Sundström J, Lind L, Franzon K, Kilander L, Benedict CReverse Dipping of Systolic Blood Pressure Is Associated With Increased Dementia Risk in Older Men: A Longitudinal Study Over 24 Years.Hypertension.(2021-04)
    54. ^de Heus RAA, Tzourio C, Lee EJL, Opozda M, Vincent AD, Anstey KJ, Hofman A, Kario K, Lattanzi S, Launer LJ, Ma Y, Mahajan R, Mooijaart SP, Nagai M, Peters R, Turnbull D, Yano Y, , Claassen JAHR, Tully PJAssociation Between Blood Pressure Variability With Dementia and Cognitive Impairment: A Systematic Review and Meta-Analysis.Hypertension.(2021-11)
    55. ^Gosztyla ML, Brothers HM, Robinson SRAlzheimer's Amyloid-β is an Antimicrobial Peptide: A Review of the Evidence.J Alzheimers Dis.(2018)
    56. ^Steel AJ, Eslick GDHerpes Viruses Increase the Risk of Alzheimer's Disease: A Meta-Analysis.J Alzheimers Dis.(2015)
    57. ^Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, György B, Breakefield XO, Tanzi RE, Moir RDAlzheimer's Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection.Neuron.(2018-07-11)
    58. ^Kamer AR, Craig RG, Niederman R, Fortea J, de Leon MJPeriodontal disease as a possible cause for Alzheimer's disease.Periodontol 2000.(2020-06)
    59. ^Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, Nguyen M, Haditsch U, Raha D, Griffin C, Holsinger LJ, Arastu-Kapur S, Kaba S, Lee A, Ryder MI, Potempa B, Mydel P, Hellvard A, Adamowicz K, Hasturk H, Walker GD, Reynolds EC, Faull RLM, Curtis MA, Dragunow M, Potempa Jin Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors.Sci Adv.(2019-01)
    60. ^Jeffrey J Iliff, Minghuan Wang, Yonghong Liao, Benjamin A Plogg, Weiguo Peng, Georg A Gundersen, Helene Benveniste, G Edward Vates, Rashid Deane, Steven A Goldman, Erlend A Nagelhus, Maiken NedergaardA paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid βSci Transl Med.(2012 Aug 15)
    61. ^Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard MSleep drives metabolite clearance from the adult brainScience.(2013 Oct 18)
    62. ^Fan L, Xu W, Cai Y, Hu Y, Wu CSleep Duration and the Risk of Dementia: A Systematic Review and Meta-analysis of Prospective Cohort Studies.J Am Med Dir Assoc.(2019-12)
    63. ^Kurina LM, McClintock MK, Chen JH, Waite LJ, Thisted RA, Lauderdale DSSleep duration and all-cause mortality: a critical review of measurement and associations.Ann Epidemiol.(2013-Jun)
    64. ^Wang C, Holtzman DMBidirectional relationship between sleep and Alzheimer's disease: role of amyloid, tau, and other factors.Neuropsychopharmacology.(2020-01)
    65. ^Omonigho M Bubu, Michael Brannick, James Mortimer, Ogie Umasabor-Bubu, Yuri V Sebastião, Yi Wen, Skai Schwartz, Amy R Borenstein, Yougui Wu, David Morgan, William M AndersonSleep, Cognitive impairment, and Alzheimer's disease: A Systematic Review and Meta-AnalysisSleep.(2017 Jan 1)
    66. ^Natalia García-Casares, Paloma Gallego Fuentes, Miguel Ángel Barbancho, Rosa López-Gigosos, Antonio García-Rodríguez, Mario Gutiérrez-BedmarAlzheimer's Disease, Mild Cognitive Impairment and Mediterranean Diet. A Systematic Review and Dose-Response Meta-AnalysisJ Clin Med.(2021 Oct 10)
    67. ^Martha Clare Morris, Christy C Tangney, Yamin Wang, Frank M Sacks, David A Bennett, Neelum T AggarwalMIND diet associated with reduced incidence of Alzheimer's diseaseAlzheimers Dement.(2015 Sep)
    68. ^Miao H, Chen K, Yan X, Chen FSugar in Beverage and the Risk of Incident Dementia, Alzheimer's Disease and Stroke: A Prospective Cohort Study.J Prev Alzheimers Dis.(2021)
    69. ^Shunquan Wu, Yingying Ding, Fuquan Wu, Ruisheng Li, Jun Hou, Panyong MaoOmega-3 fatty acids intake and risks of dementia and Alzheimer's disease: a meta-analysisNeurosci Biobehav Rev.(2015 Jan)
    70. ^Samieri C, Morris MC, Bennett DA, Berr C, Amouyel P, Dartigues JF, Tzourio C, Chasman DI, Grodstein FFish Intake, Genetic Predisposition to Alzheimer Disease, and Decline in Global Cognition and Memory in 5 Cohorts of Older Persons.Am J Epidemiol.(2018-05-01)
    71. ^Susanna C Larsson, Nicola OrsiniCoffee Consumption and Risk of Dementia and Alzheimer's Disease: A Dose-Response Meta-Analysis of Prospective StudiesNutrients.(2018 Oct 14)
    72. ^Yuan Zhang, Hongxi Yang, Shu Li, Zhi Cao, Wei-Dong Li, Tao Yan, Yaogang WangAssociation of coffee and genetic risk with incident dementia in middle-aged and elderly adultsNutr Neurosci.(2021 Aug 23)
    73. ^Anstey KJ, Mack HA, Cherbuin NAlcohol consumption as a risk factor for dementia and cognitive decline: meta-analysis of prospective studies.Am J Geriatr Psychiatry.(2009-Jul)
    74. ^Xu W, Tan L, Wang HF, Jiang T, Tan MS, Tan L, Zhao QF, Li JQ, Wang J, Yu JTMeta-analysis of modifiable risk factors for Alzheimer's disease.J Neurol Neurosurg Psychiatry.(2015-Dec)
    75. ^Costanzo S, de Gaetano G, Di Castelnuovo A, Djoussé L, Poli A, van Velden DPModerate alcohol consumption and lower total mortality risk: Justified doubts or established facts?Nutr Metab Cardiovasc Dis.(2019-10)
    76. ^Andrews SJ, Goate A, Anstey KJAssociation between alcohol consumption and Alzheimer's disease: A Mendelian randomization study.Alzheimers Dement.(2020-02)
    77. ^Kivimäki M, Singh-Manoux A, Batty GD, Sabia S, Sommerlad A, Floud S, Jokela M, Vahtera J, Beydoun MA, Suominen SB, Koskinen A, Väänänen A, Goldberg M, Zins M, Alfredsson L, Westerholm PJM, Knutsson A, Nyberg ST, Sipilä PN, Lindbohm JV, Pentti J, Livingston G, Ferrie JE, Strandberg TAssociation of Alcohol-Induced Loss of Consciousness and Overall Alcohol Consumption With Risk for Dementia.JAMA Netw Open.(2020-09-01)
    78. ^Zuin M, Cervellati C, Brombo G, Trentini A, Roncon L, Zuliani GElevated Blood Homocysteine and Risk of Alzheimer's Dementia: An Updated Systematic Review and Meta-Analysis Based on Prospective Studies.J Prev Alzheimers Dis.(2021)
    79. ^Jevtic S, Sengar AS, Salter MW, McLaurin JThe role of the immune system in Alzheimer disease: Etiology and treatment.Ageing Res Rev.(2017-Nov)
    80. ^Wang L, Qiao Y, Zhang H, Zhang Y, Hua J, Jin S, Liu GCirculating Vitamin D Levels and Alzheimer's Disease: A Mendelian Randomization Study in the IGAP and UK Biobank.J Alzheimers Dis.(2020)
    81. ^Larsson SC, Traylor M, Markus HS, Michaëlsson KSerum Parathyroid Hormone, 25-Hydroxyvitamin D, and Risk of Alzheimer's Disease: A Mendelian Randomization Study.Nutrients.(2018-Sep-06)
    82. ^Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MAOxidative damage is the earliest event in Alzheimer disease.J Neuropathol Exp Neurol.(2001-Aug)
    83. ^Gella A, Durany NOxidative stress in Alzheimer disease.Cell Adh Migr.(2009)
    84. ^Dyall SCLong-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA.Front Aging Neurosci.(2015)
    85. ^Yan L, Xie Y, Satyanarayanan SK, Zeng H, Liu Q, Huang M, Ma Y, Wan JB, Yao X, Su KP, Su HOmega-3 polyunsaturated fatty acids promote brain-to-blood clearance of β-Amyloid in a mouse model with Alzheimer's disease.Brain Behav Immun.(2020-03)
    86. ^Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N, Frautschy SA, Cole GMA diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model.J Neurosci.(2005-Mar-23)
    87. ^Ibach B, Haen EAcetylcholinesterase inhibition in Alzheimer's Disease.Curr Pharm Des.(2004)
    88. ^Ameneh Mashayekh, Dzung L Pham, David M Yousem, Mercedes Dizon, Peter B Barker, Doris D M LinEffects of Ginkgo biloba on cerebral blood flow assessed by quantitative MR perfusion imaging: a pilot studyNeuroradiology.(2011 Mar)
    89. ^Shi C, Liu J, Wu F, Yew DTGinkgo biloba extract in Alzheimer's disease: from action mechanisms to medical practice.Int J Mol Sci.(2010-Jan-08)
    90. ^Kim HJ, Shin EJ, Lee BH, Choi SH, Jung SW, Cho IH, Hwang SH, Kim JY, Han JS, Chung C, Jang CG, Rhim H, Kim HC, Nah SYOral Administration of Gintonin Attenuates Cholinergic Impairments by Scopolamine, Amyloid-β Protein, and Mouse Model of Alzheimer's Disease.Mol Cells.(2015-Sep)
    91. ^Kim HJ, Kim DJ, Shin EJ, Lee BH, Choi SH, Hwang SH, Rhim H, Cho IH, Kim HC, Nah SYEffects of gintonin-enriched fraction on hippocampal cell proliferation in wild-type mice and an APPswe/PSEN-1 double Tg mouse model of Alzheimer's disease.Neurochem Int.(2016-12)
    92. ^Zhang J, Wang Y, Dong X, Liu JCrocetin attenuates inflammation and amyloid-β accumulation in APPsw transgenic mice.Immun Ageing.(2018)
    93. ^Asadi F, Jamshidi AH, Khodagholi F, Yans A, Azimi L, Faizi M, Vali L, Abdollahi M, Ghahremani MH, Sharifzadeh MReversal effects of crocin on amyloid β-induced memory deficit: Modification of autophagy or apoptosis markers.Pharmacol Biochem Behav.(2015-Dec)
    94. ^Batarseh YS, Bharate SS, Kumar V, Kumar A, Vishwakarma RA, Bharate SB, Kaddoumi ACrocus sativus Extract Tightens the Blood-Brain Barrier, Reduces Amyloid β Load and Related Toxicity in 5XFAD Mice.ACS Chem Neurosci.(2017-08-16)
    95. ^Hadipour M, Kaka G, Bahrami F, Meftahi GH, Pirzad Jahromi G, Mohammadi A, Sahraei HCrocin improved amyloid beta induced long-term potentiation and memory deficits in the hippocampal CA1 neurons in freely moving rats.Synapse.(2018-05)
    96. ^Wang X, Sun G, Feng T, Zhang J, Huang X, Wang T, Xie Z, Chu X, Yang J, Wang H, Chang S, Gong Y, Ruan L, Zhang G, Yan S, Lian W, Du C, Yang D, Zhang Q, Lin F, Liu J, Zhang H, Ge C, Xiao S, Ding J, Geng MSodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer's disease progression.Cell Res.(2019-Oct)
    97. ^Christian-Alexandre Castellano, Scott Nugent, Nancy Paquet, Sébastien Tremblay, Christian Bocti, Guy Lacombe, Hélène Imbeault, Éric Turcotte, Tamas Fulop, Stephen C CunnaneLower brain 18F-fluorodeoxyglucose uptake but normal 11C-acetoacetate metabolism in mild Alzheimer's disease dementiaJ Alzheimers Dis.(2015)
    98. ^Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LCStudy of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trialNutr Metab (Lond).(2009 Aug 10)
    99. ^Matthew C L Phillips, Laura M Deprez, Grace M N Mortimer, Deborah K J Murtagh, Stacey McCoy, Ruth Mylchreest, Linda J Gilbertson, Karen M Clark, Patricia V Simpson, Eileen J McManus, Jee-Eun Oh, Satish Yadavaraj, Vanessa M King, Avinesh Pillai, Beatriz Romero-Ferrando, Martijn Brinkhuis, Bronwyn M Copeland, Shah Samad, Shenyang Liao, Jan A C SchepelRandomized crossover trial of a modified ketogenic diet in Alzheimer's diseaseAlzheimers Res Ther.(2021 Feb 23)

    Examine Database References

    1. Alzheimer's Disease Symptoms - Jingya Jia, Jing Hu, Xiaoxu Huo, Rujuan Miao, Yanping Zhang, Fei MaEffects of vitamin D supplementation on cognitive function and blood Aβ-related biomarkers in older adults with Alzheimer's disease: a randomised, double-blind, placebo-controlled trialJ Neurol Neurosurg Psychiatry.(2019 Dec)
    2. Alzheimer's Disease Symptoms - I-Chen Li, Han-Hsin Chang, Chuan-Han Lin, Wan-Ping Chen, Tsung-Han Lu, Li-Ya Lee, Yu-Wen Chen, Yen-Po Chen, Chin-Chu Chen, David Pei-Cheng LinPrevention of Early Alzheimer's Disease by Erinacine A-Enriched Hericium erinaceus Mycelia Pilot Double-Blind Placebo-Controlled StudyFront Aging Neurosci.(2020 Jun 3)
    3. Alzheimer's Disease Symptoms - Soon-Tae Lee, Kon Chu, Ji-Young Sim, Jae-Hyeok Heo, Manho KimPanax ginseng enhances cognitive performance in Alzheimer diseaseAlzheimer Dis Assoc Disord.(Jul-Sep 2008)
    4. Alzheimer's Disease Symptoms - Jae-Hyeok Heo, Soon-Tae Lee, Min Jung Oh, Hyun-Jung Park, Ji-Young Shim, Kon Chu, Manho KimImprovement of cognitive deficit in Alzheimer's disease patients by long term treatment with korean red ginsengJ Ginseng Res.(2011 Nov)
    5. Alzheimer's Disease Symptoms - Jae-Hyeok Heo, Soon-Tae Lee, Kon Chu, Min Jung Oh, Hyun-Jung Park, Ji-Young Shim, Manho KimHeat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's diseaseNutr Neurosci.(2012 Nov)
    6. Alzheimer's Disease Symptoms - Lee, Soon-Tae., Chu, Kon., Kim, Jeong-Min., Park, Hyun-Jeong., Kim, Man-Ho Cognitive improvement by ginseng in Alzheimer's diseaseJournal of Ginseng Research.()
    7. Cognitive Decline - Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, Kim MAn open-label trial of Korean red ginseng as an adjuvant treatment for cognitive impairment in patients with Alzheimer's diseaseEur J Neurol.(2008 Aug)
    8. Alzheimer's Disease Symptoms - Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M, Love S, Schellenberg GD, McCarten JR, Malphurs J, Prieto S, Chen P, Loreck DJ, Trapp G, Bakshi RS, Mintzer JE, Heidebrink JL, Vidal-Cardona A, Arroyo LM, Cruz AR, Zachariah S, Kowall NW, Chopra MP, Craft S, Thielke S, Turvey CL, Woodman C, Monnell KA, Gordon K, Tomaska J, Segal Y, Peduzzi PN, Guarino PDEffect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trialJAMA.(2014 Jan 1)
    9. Alzheimer's Disease Symptoms - Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman CW, Pfeiffer E, Schneider LS, Thal LJA controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative StudyN Engl J Med.(1997 Apr 24)
    10. Alzheimer's Disease Risk - Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ, Alzheimer's Disease Cooperative Study GroupVitamin E and donepezil for the treatment of mild cognitive impairmentN Engl J Med.(2005 Jun 9)
    11. Alzheimer's Disease Symptoms - Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, Van Dyck C, Galvin JE, Emond J, Jack CR Jr, Weiner M, Shinto L, Aisen PSDocosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trialJAMA.(2010 Nov 3)
    12. Alzheimer's Disease Symptoms - Green RC, Goldstein FC, Auchus AP, Presley R, Clark WS, Van Tuyl L, Green J, Hersch SM, Karp HRTreatment trial of oxiracetam in Alzheimer's diseaseArch Neurol.(1992 Nov)
    13. Alzheimer's Disease Symptoms - Akhondzadeh S, Sabet MS, Harirchian MH, Togha M, Cheraghmakani H, Razeghi S, Hejazi SSh, Yousefi MH, Alimardani R, Jamshidi A, Zare F, Moradi ASaffron in the treatment of patients with mild to moderate Alzheimer's disease: a 16-week, randomized and placebo-controlled trialJ Clin Pharm Ther.(2010 Oct)
    14. Alzheimer's Disease Symptoms - Mehdi Farokhnia, Mehdi Shafiee Sabet, Negar Iranpour, Amirhossein Gougol, Habibeh Yekehtaz, Roozbeh Alimardani, Farzaneh Farsad, Maryam Kamalipour, Shahin AkhondzadehComparing the efficacy and safety of Crocus sativus L. with memantine in patients with moderate to severe Alzheimer's disease: a double-blind randomized clinical trialHum Psychopharmacol.(2014 Jul)
    15. Alzheimer's Disease Symptoms - Akhondzadeh S, Shafiee Sabet M, Harirchian MH, Togha M, Cheraghmakani H, Razeghi S, Hejazi SS, Yousefi MH, Alimardani R, Jamshidi A, Rezazadeh SA, Yousefi A, Zare F, Moradi A, Vossoughi AA 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of mild-to-moderate Alzheimer's diseasePsychopharmacology (Berl).(2010 Jan)
    16. Alzheimer's Disease Symptoms - Sudesh Prabhakar, Venugopalan Y Vishnu, Manish Modi, Manju Mohanty, Anchal Sharma, Bikas Medhi, B R Mittal, Niranjan Khandelwal, Manoj K Goyal, Vivek Lal, Rajesh Singla, Avinash Kansal, Ajit AvasthiEfficacy of Bacopa Monnieri (Brahmi) and Donepezil in Alzheimer's Disease and Mild Cognitive Impairment: A Randomized Double-Blind Parallel Phase 2b StudyAnn Indian Acad Neurol.(Nov-Dec 2020)
    17. Alzheimer's Disease Symptoms - Herrschaft H, Nacu A, Likhachev S, Sholomov I, Hoerr R, Schlaefke SGinkgo biloba extract EGb 761® in dementia with neuropsychiatric features: a randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of 240 mgJ Psychiatr Res.(2012 Jun)
    18. Alzheimer's Disease Symptoms - Ihl R, Tribanek M, Bachinskaya N, GOTADAY Study GroupEfficacy and tolerability of a once daily formulation of Ginkgo biloba extract EGb 761® in Alzheimer's disease and vascular dementia: results from a randomised controlled trialPharmacopsychiatry.(2012 Mar)
    19. Cognitive Decline - Yancheva S, Ihl R, Nikolova G, Panayotov P, Schlaefke S, Hoerr R, GINDON Study GroupGinkgo biloba extract EGb 761(R), donepezil or both combined in the treatment of Alzheimer's disease with neuropsychiatric features: a randomised, double-blind, exploratory trialAging Ment Health.(2009 Mar)
    20. Cognitive Decline - Vellas B, Coley N, Ousset PJ, Berrut G, Dartigues JF, Dubois B, Grandjean H, Pasquier F, Piette F, Robert P, Touchon J, Garnier P, Mathiex-Fortunet H, Andrieu S, GuidAge Study GroupLong-term use of standardised Ginkgo biloba extract for the prevention of Alzheimer's disease (GuidAge): a randomised placebo-controlled trialLancet Neurol.(2012 Oct)
    21. Alzheimer's Disease Symptoms - Barak Y, Levine J, Glasman A, Elizur A, Belmaker RHInositol treatment of Alzheimer's disease: a double blind, cross-over placebo controlled trialProg Neuropsychopharmacol Biol Psychiatry.(1996 May)
    22. Alzheimer's Disease Symptoms - Salloway S, Sperling R, Keren R, Porsteinsson AP, van Dyck CH, Tariot PN, Gilman S, Arnold D, Abushakra S, Hernandez C, Crans G, Liang E, Quinn G, Bairu M, Pastrak A, Cedarbaum JM, ELND005-AD201 InvestigatorsA phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer diseaseNeurology.(2011 Sep 27)
    23. Alzheimer's Disease Symptoms - De Jesus Moreno Moreno MCognitive improvement in mild to moderate Alzheimer's dementia after treatment with the acetylcholine precursor choline alfoscerate: a multicenter, double-blind, randomized, placebo-controlled trialClin Ther.(2003 Jan)
    24. Cognitive Decline - Engel RR, Satzger W, Günther W, Kathmann N, Bove D, Gerke S, Münch U, Hippius HDouble-blind cross-over study of phosphatidylserine vs. placebo in patients with early dementia of the Alzheimer typeEur Neuropsychopharmacol.(1992 Jun)
    25. Cognitive Decline - Crook T, Petrie W, Wells C, Massari DCEffects of phosphatidylserine in Alzheimer's diseasePsychopharmacol Bull.(1992)
    26. Cognitive Decline - Klinkhammer P, Szelies B, Heiss W.D.Effect of Phosphatidylserine on Cerebral Glucose Metabolism in Alzheimer's DiseaseDementia and Geriatric Cognitive Disorders.()
    27. Cognitive Decline - Dubois B, Zaim M, Touchon J, Vellas B, Robert P, Murphy MF, Pujadas-Navinés F, Rainer M, Soininen H, Riordan HJ, Kanony-Truc CEffect of six months of treatment with V0191 in patients with suspected prodromal Alzheimer's diseaseJ Alzheimers Dis.(2012)
    28. Cognitive Decline - Baum L, Lam CW, Cheung SK, Kwok T, Lui V, Tsoh J, Lam L, Leung V, Hui E, Ng C, Woo J, Chiu HF, Goggins WB, Zee BC, Cheng KF, Fong CY, Wong A, Mok H, Chow MS, Ho PC, Ip SP, Ho CS, Yu XW, Lai CY, Chan MH, Szeto S, Chan IH, Mok VSix-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer diseaseJ Clin Psychopharmacol.(2008 Feb)
    29. Cognitive Decline - Croisile B, Trillet M, Fondarai J, Laurent B, Mauguière F, Billardon MLong-term and high-dose piracetam treatment of Alzheimer's diseaseNeurology.(1993 Feb)
    30. Cognition - Chiu S, Gericke N, Farina-Woodbury M, Badmaev V, Raheb H, Terpstra K, Antongiorgi J, Bureau Y, Cernovsky Z, Hou J, Sanchez V, Williams M, Copen J, Husni M, Goble LProof-of-Concept Randomized Controlled Study of Cognition Effects of the Proprietary Extract Sceletium tortuosum (Zembrin) Targeting Phosphodiesterase-4 in Cognitively Healthy Subjects: Implications for Alzheimer's DementiaEvid Based Complement Alternat Med.(2014)
    31. Dementia Symptoms - Lott IT, Doran E, Nguyen VQ, Tournay A, Head E, Gillen DLDown syndrome and dementia: a randomized, controlled trial of antioxidant supplementationAm J Med Genet A.(2011 Aug)
    32. C-Reactive Protein (CRP) - Armita Mahdavi Gorabi, Saeed Aslani, Danyal Imani, Bahman Razi, Thozhukat Sathyapalan, Amirhossein SahebkarEffect of resveratrol on C-reactive protein: An updated meta-analysis of randomized controlled trialsPhytother Res.(2021 Dec)
    33. Weight - Mousavi SM, Milajerdi A, Sheikhi A, Kord-Varkaneh H, Feinle-Bisset C, Larijani B, Esmaillzadeh AResveratrol supplementation significantly influences obesity measures: a systematic review and dose-response meta-analysis of randomized controlled trials.Obes Rev.(2019-Mar)