What is Cognitive Decline & Mild Cognitive Impairment?

Aging is associated with a gradual decline in cognitive function and thinking skills. As such, it is common for aging individuals to find that mental tasks take longer to complete and their memory and attention may be diminished. Age-related cognitive decline is a complex process with numerous contributing factors, including cellular senescence, disturbances of the circadian rhythm, and neuroinflammation, among others.

Age-related cognitive decline may progress more than expected for the person’s age but not become severe enough to be called dementia. In this situation, the condition is called mild cognitive impairment (MCI). In contrast, dementia refers to cognitive decline that is severe enough that it becomes debilitating, interfering with the person’s ability to function independently.

Fortunately, proactive lifestyle changes, cognitive training, and nutrients, such as bacopa and huperzine A, have been shown to decrease the rate of intellectual decay and potentially reverse age-related cognitive decline.

Nutrients

• Ginkgo. Numerous clinical trials and meta-analyses have demonstrated Ginkgo biloba’s ability to slow cognitive decline. An expert consensus paper from 2019 concluded that ginkgo is safe and effective and can be recommended alone or in combination with conventional therapies to treat mild cognitive impairment and dementia.
• Bacopa. Bacopa monnieri, a plant used in Ayurvedic medicine for centuries, has been shown in many clinical trials to improve several aspects of cognition.
• Huperzine A. Huperzine A, a compound from the medicinal herb Huperzia serrata, has been shown to inhibit acetylcholinesterase, an enzyme that breaks down the neurotransmitter acetylcholine. Patients with dementia and Alzheimer disease improved their scores on standard cognitive tests after supplementing with huperzine A.
• Acetyl-L-carnitine. Decreasing levels of acetyl-L-carnitine have been associated with a decline in cognitive function. A meta-analysis of data from over 21 studies showed supplementation with acetyl-L-carnitine improved cognitive deficits in patients with mild cognitive impairment and Alzheimer disease.
• Magnesium-L-threonate. Magnesium-L-threonate is a form of magnesium found to effectively raise brain magnesium levels. Preclinical research indicates it can protect brain function and preserve neural connections.
• Phosphatidylserine. Phosphatidylserine is a phospholipid that is an important part of myelin and cell membranes. Clinical trials indicate supplementing with phosphatidylserine can improve cognitive function in aging subjects with cognitive impairment.
• Alpha-glyceryl phosphoryl choline (α-GPC). α-GPC serves as a precursor to the neurotransmitter acetylcholine. Acetylcholine precursors, alone or in combination with acetylcholinesterase inhibitors, are promising for treating dementia.
• Mango leaf extract. Mango leaf extracts rich in mangiferin have anti-inflammatory and neuroprotective properties. An extract standardized to 60% mangiferin was shown in clinical studies to improve various aspects of cognition, including episodic memory and visual information processing.
• Peppermint oil. Peppermint essential oil is rich in monoterpenes, which are known for their benefits to cognition. Peppermint oil inhibits acetylcholinesterase and was shown in a clinical trial to improve performance on a cognitively demanding task and prevent cognitive fatigue.
• Other natural interventions that may benefit brain health and overall cognitive function include polyphenols, melatonin, B vitamins, colostrinin, lithium, and more.

What Dietary & Lifestyle Changes Support Brain Health?

• Switch from a Western-style diet (high in simple sugars and saturated fats) to a healthy dietary pattern such as the Mediterranean, DASH, or MIND diet
• Caloric restriction may improve learning and memory
• Cognitive stimulation and training, including playing chess and speaking more than one language, can enhance cognitive reserve and convey protection against loss of brain function, supporting healthy cognitive function into older age
• Manage stress and get enough quality sleep
• Engage in social activities (strong social networks promote cognitive health)
• Exercise is known to increase levels of brain-derived neurotrophic factor, which can lead to enhanced cognitive function
• Moderate caffeine and coffee consumption (1‒2 cups/day) may convey protection against cognitive decline

What are the Symptoms of Cognitive Decline?

Those who experience cognitive decline may have difficulty with various aspects of cognition, including:

• Planning and organizing
• Following changes in conversation
• Finding words
• Focusing
• Losing items
• Loss of empathy or judgement
• Inappropriate behavior

Additionally, mood changes are common, with depression affecting approximately one-third of those with mild cognitive impairment.

What Increases the Risk of Cognitive Decline?

• Age
• Sedentary lifestyle
• Low level of education
• Smoking
• Obesity
• Insulin resistance/type 2 diabetes
• High blood pressure
• High cholesterol
• Depression
• Sleep disorders
• Sleep apnea
• Chronic kidney disease
• Cardiovascular disease
• Cerebrovascular disease including history of stroke
• Traumatic brain injury
• Hearing loss
• Female gender (women seem to be more likely to experience cognitive decline than men)

Nootropic Drugs & Novel Approaches to Cognitive Decline

There are not currently any medications specifically approved for age-related cognitive decline. Anti-dementia medications do not appear to prevent progression from mild cognitive impairment to dementia. However, certain medications have been found to have brain-protective or enhancing effects:

• Piracetam and levetiracetam (anti-seizure medications)
• Selegiline (medication used for Parkinson’s, Alzheimer, and major depressive disorder)
• Zileuton (asthma medication)
• Angiotensin receptor blockers (eg, candesartan)

Cognitive function peaks around age 20 and diminishes steadily over the remaining years of life.^1,2 With life expectancies increasing dramatically in the last century, cognitive decline, mild cognitive impairment (MCI), and dementia have become major concerns.^3,4

Aging is associated with gradual changes in the brain that impair its function. As a result, older people, even those without overt neurological disease, often find it takes longer to perform mental tasks and experience diminished memory, attention, and abilities to learn, reason, and solve problems.² Although some cognitive decline occurs during normal aging, its rate of progression is affected by lifestyle, dietary, environmental, and genetic factors.⁵ Importantly, some of these factors that contribute to the progression of cognitive decline are modifiable.^1,6

Some factors that likely contribute to cognitive decline include:

• Stem cell senescence
• Brain oxidative stress and mitochondrial dysfunction
• Neuroinflammation (inflammation in the brain)
• Circadian rhythm and metabolic disturbances
• Vascular dysfunction
• Abnormal protein accumulation in the brain
• Disordered homocysteine metabolism
• Changing hormone levels
• Epigenetic factors—changes in the way genes are expressed

These same mechanisms also appear to contribute to dementia and neurodegenerative diseases like Alzheimer disease and Parkinson disease.¹

Much is known about lifestyle factors that work together to promote healthy brain aging, such as eating a nutrient-dense diet (eg, Mediterranean, MIND, or DASH diet), being physically active, reducing stress, getting adequate sleep, and regularly engaging in mentally and socially stimulating activities.^1,4,6 In addition, a number of integrative interventions have been identified as having protective effects on brain function.^7,8

This protocol will review many underlying factors that contribute to cognitive decline, and describe several novel medical strategies, lifestyle and dietary habits, and integrative interventions that can support healthy cognitive function and brain health throughout life.

The brain contains approximately 100 billion interconnected neurons, which collectively assimilate information received from nerves throughout the body and external stimuli. In addition to neurons, the brain is home to specialized cells known as glial cells, mainly astrocytes and microglia, which play numerous essential support roles.^9,10 Glial cells also participate in vital signaling processes within the brain.¹¹

The Aging Brain

With age, the number of brain neurons decreases and the cells and tissues that support them deteriorate slowly after age 20 and more rapidly after age 60. By age 90, brain mass has been found to be decreased by 11% compared with individuals in their 50s.⁵ The majority of neuronal loss is in the cerebral cortex, where most information processing occurs, and the hippocampus, a brain structure involved in memory and learning.^2,12,13

Aging is associated with functional brain changes as well. For instance, cerebral blood flow decreases and production of neurotransmitters is reduced. Also, the integrity of the blood‒brain barrier, which controls movement of cells and molecules into and out of blood vessels in the brain, weakens,^2,14 and the phospholipid-rich myelin sheaths that protect neurons and facilitate signal transmission deteriorate.^13,15

These age-related brain changes manifest in the diminished mental abilities and thinking skills typically associated with old age, namely reduced short-term and episodic memory, difficulty recalling words, slower reaction times, and possibly depressed mood.²

From Age-Related Cognitive Decline to Mild Cognitive Impairment and Dementia

Age-related cognitive decline describes the natural decline in ability to learn, remember, and process information. Mild cognitive impairment (MCI) is the condition characterized by cognitive changes that are more than expected for age, but not debilitating. It is estimated that 10–20% of adults aged 65 years and older have MCI.^16,17 There are two broad classifications of MCI: amnestic MCI and non-amnestic MCI.⁵⁴⁷

• Amnestic MCI describes cognitive changes that include memory problems that are not significant enough to be classified as dementia. Amnestic MCI is the most common type of MCI and is often considered a precursor to Alzheimer disease, although not all people with amnestic MCI will progress to Alzheimer disease.
• Non-amnestic MCI describes cognitive changes in domains other than memory, such as language, executive functioning, and visual-spatial skills. This form of MCI is about half as common as amnestic MCI.

When cognitive decline becomes severe enough to interfere with social and occupational function and the ability to live independently, the condition is called dementia.^17,18 Dementia affects approximately 5–10% of US adults age 65 and older.^17,19 Alzheimer disease is the most common form of dementia in the elderly, followed by cerebrovascular dysfunction.¹⁴ Importantly, most people with age-related losses in cognitive function never develop these more advanced conditions.^18,20

Distinguishing between normal age-related cognitive issues and mild cognitive impairment is challenging. A comprehensive assessment that includes a history of cognitive changes, physical exam, neurological exam, and cognitive function testing is essential to an accurate diagnosis.¹⁸ A standardized assessment of cognitive function known as the Mini-Mental State Examination (MMSE) is one such example of a test that may be performed. The MMSE is scored on a 30-point scale and assesses verbal, memory, and constructional functions. An MMSE score of less than 24 is commonly considered abnormal and indicative of dementia; scores of 24–27 may indicate MCI and increased risk of progression to dementia in the future (see Figure 1).^548-550 Laboratory testing, including screening for hypothyroidism and vitamin B12 deficiency, will help determine if common treatable conditions are contributing factors to cognitive decline.

Figure 1: Trajectories of cognitive function with normal age-related cognitive decline, MCI, and dementia over time

Table 1: Domains of cognitive decline and functional signs of impairment17
Cognitive Domain	Signs of Impairment
Executive function	Difficulties with: Planning Organizing Multitasking Following directions Keeping up with shifting conversations
Attention	Normal tasks take longer or need to be simplified Difficulty focusing in conditions with multiple stimuli Distractibility Difficulty holding information in mind for tasks such as mental calculations or dialing a phone number
Visuospatial skills	Getting lost in familiar places Difficulty using familiar tools or appliances Increasing need for notes and maps
Language	Difficulty finding words Using words or phrases wrong Difficulty with written and verbal language comprehension More frequent grammatical errors
Memory and learning	Difficulty remembering recent events Repeating oneself Misplacing items Losing track of actions that have already been done Increasing need for lists and reminders
Social cognition	Disinhibition or apathy Loss of empathy Inappropriate behavior Loss of judgement

Figure 2: Examples of nutrients shown to support brain health.

Ginkgo

Ginkgo (Ginkgo biloba) is perhaps the most widely studied and commonly used integrative therapy for supporting cognitive function. Ginkgo extracts have been shown to reduce oxidative stress, decrease neuroinflammation, improve microcirculation, modulate neurotransmitter activity, and promote neuroplasticity.^228,229 Animal research suggests ginkgo may stimulate neural stem cell proliferation and activity.²³⁰

Numerous randomized controlled trials, systematic reviews, and meta-analyses have concluded that ginkgo, usually at a dose of 120‒240 mg per day, can slow cognitive decline and reduce neuropsychiatric symptoms (such as delusions and depressed or anxious mood) in patients with mild cognitive impairment and dementia.^228,231-233 A 2019 expert consensus paper found the evidence of efficacy and safety sufficient to recommend a standardized ginkgo extract, alone or in combination with conventional therapies, for treatment of mild cognitive impairment and dementia.²³⁴

Bacopa

Bacopa (Bacopa monnieri), a plant with religious, cultural, and medical importance in India, has been used in traditional Ayurvedic medicine for centuries.²³⁵ Bacopa extract has demonstrated effects such as reducing brain oxidative stress, modulating neurotransmitter activity, reducing β-amyloid deposition, strengthening neuronal connections, and increasing cerebral blood flow in preclinical research.^236,237 Human research suggests bacopa may also improve the stress response.²³⁸ Furthermore, in mice, bacopa extract increased brain levels of brain-derived neurotrophic factor (BDNF) and production of new neurons.²³⁹

A meta-analysis that included data from 518 subjects in nine randomized controlled trials concluded bacopa has the potential to improve some aspects of cognition.²⁴⁰ In one randomized controlled trial in 54 participants aged 65 years and older, those who received 300 mg bacopa extract daily for 12 weeks had better cognitive performance and reduced symptoms of anxiety and depression after 12 weeks compared with placebo.²⁴¹ Two clinical trials using different herb-nutrient combinations with bacopa reported cognitive benefits from treatment with these supplements in older adults with mild cognitive impairment.^242,243

Huperzine A

Huperzine A is a biologically active compound from the Chinese medicinal herb Huperzia serrata, commonly known as Chinese club moss. Huperzine A has been shown to inhibit acetylcholinesterase, an enzyme that breaks down acetylcholine. Acetylcholine is a major neurotransmitter in the autonomic nervous system, and its accelerated breakdown by acetylcholinesterase is thought to contribute to age-related cognitive decline and dementia.²⁴⁴ Some anti-dementia drugs like donepezil (Aricept) also work by inhibiting acetylcholinesterase, and huperzine A has been proposed to have a disease-modifying effect in Alzheimer disease.²⁴⁵ In addition, preclinical evidence suggests huperzine A may reduce oxidative stress, prevent β-amyloid and phosphorylated tau accumulation, support mitochondrial function, and increase brain production of nerve growth factor.²⁴⁶

Numerous clinical trials have shown that huperzine A can improve cognitive function in people with dementia. One meta-analysis included 10 randomized controlled trials evaluating the effects of huperzine A, in doses ranging from 100–400 mcg daily, in a combined total of 825 patients with Alzheimer or vascular dementia. The results of the analysis indicated huperzine A can improve cognitive function in dementia patients, and longer use may result in greater benefits.²⁴⁷ Another meta-analysis of 20 randomized controlled trials in Alzheimer disease patients also noted likely benefits of huperzine A on cognitive function.²⁴⁸ One preliminary trial examined the effect of huperzine A on task switching, a higher-order cognitive function, in patients with Alzheimer disease. After eight weeks of treatment with 200 mcg huperzine A, cognitive function and performance on task switching tests improved.²⁴⁹ In another preliminary trial, a supplement containing huperzine A and curcumin improved cognitive performance after 6–12 and 22–28 weeks in people with dementia as well as those with mild cognitive impairment.²⁵⁰

It should be noted that mild adverse side effects such as digestive upset and constipation, dizziness, slow heart rate, and dry mouth have been reported by people taking huperzine A.^247,248

Acetyl-L-carnitine

Acetyl-L-carnitine is a form of the amino acid, carnitine, produced in the mitochondria and involved in cellular energy production. It also is a precursor molecule for the formation of acetylcholine.⁵⁵¹ One study reported progressively decreasing blood levels of acetyl-L-carnitine in subjects on the spectrum from no cognitive problems, to subjective memory complaints, to mild cognitive impairment, to dementia.²⁵¹ Preclinical studies suggest acetyl-L-carnitine may preserve brain mitochondrial function, reduce oxidative stress, inhibit inflammatory activity by microglial cells, and improve dopamine signaling in the nervous system.^252,253

A meta-analysis of randomized controlled trials that included data from 21 studies with over 1,200 subjects found that acetyl-L-carnitine supplementation for three months or longer was associated with clinical improvement in patients with mild cognitive impairment and early Alzheimer disease.²⁵⁴ One clinical trial in elderly participants found that treatment with acetyl-L-carnitine led to decreased physical and mental fatigue, and improved cognitive and physical function.²⁵⁵ A comparison trial found acetyl-L-carnitine worked slightly faster than fluoxetine (Prozac) and with similar efficacy in improving mild depressive symptoms in elderly individuals, an effect that may be associated with better cognitive function.²⁵⁶ A combination supplement containing acetyl-L-carnitine plus B vitamins, vitamin E, and other amino acid derivatives, taken for six months, improved cognitive function in participants with mild cognitive impairment relative to placebo.²⁵⁷

Polyphenols

Polyphenols are a family of strong oxidative-stress-reducing compounds found in plants. It is thought that the high polyphenol content of the traditional Mediterranean diet may be an important contributor to its cognitive benefits.²⁶⁵ In 652 dementia-free subjects aged 65 years and older, those with higher urinary polyphenols, indicating higher polyphenol intake, had less cognitive decline during three years of monitoring.²⁶⁶ Another study in 447 older adults with increased cardiovascular risk also noted better cognitive performance in those with greater urinary polyphenol concentrations. In addition, intake of specific polyphenol-rich foods (olive oil, coffee, walnuts, and wine) was independently linked to better performance on tests of certain aspects of cognitive function.²⁶⁵

Evidence suggests polyphenols can reduce brain oxidative stress and neuroinflammation and improve cerebrovascular function.²⁶⁷ In addition to quenching excess free radicals, polyphenols may affect signaling associated with aging, preserve neural stem cell activity, promote neuroplasticity, reduce protein accumulation, induce epigenetic changes in genes involved in synaptic plasticity, and support a healthy gut microbiome.^267-270

Flavonoids are a class of polyphenolic compounds thought to support cognitive health. In an observational study following 49,493 women from the Nurses’ Health Study from 1984‒2006 and 27,842 men from the Health Professionals Follow-up Study from 1986‒2002, higher intake of total flavonoids was associated with lower odds of subjective cognitive decline. Among men and women whose total flavonoid intake was among the top 20% of combined participants (whose flavonoid intake averaged 600 mg per day), the risk of subjective cognitive impairment was 19% lower than those whose intake was among the lowest 20% (who had an average intake of 150 mg per day). The strongest associations were observed for flavones (38% lower risk), flavanones (36%), and anthocyanins (24%). In general, flavonoid-rich foods, such as strawberries, oranges, grapefruits, citrus juices, apples/pears, celery, peppers, and bananas, were significantly associated with lower odds of subjective cognitive decline.⁵³⁶

Berry polyphenols. Blueberries and their polyphenols, especially the anthocyanins that give them their color, may have preventive effects against chronic diseases including cognitive disorders.²⁷¹ Studies in older adults have shown that blueberries can enhance cerebral blood flow and increase brain activity in regions associated with age-related cognitive decline.^272,273 In a randomized controlled trial in 37 people age 60‒75 years, 24 grams of freeze dried blueberries (equivalent to one cup of fresh blueberries) daily for 90 days led to better cognitive performance compared with placebo.²⁷⁴ Another controlled trial found 24 weeks of treatment with whole-fruit blueberry powder improved cognitive function in elderly adults.²⁷⁵ In a placebo-controlled trial in 26 patients, 500 mL per day of blueberry juice at least 14 days before surgery resulted in reduced cognitive deficits associated with anesthesia.²⁷⁶ In a controlled trial in 40 healthy subjects aged 50–70 years old, taking a mixed berry drink for five weeks improved cardiovascular risk markers as well as performance on memory tests compared with placebo.²⁷⁷

Grape polyphenols. Grape polyphenols, such as quercetin, lycopene, resveratrol, and anthocyanins, have demonstrated neuroprotective actions.²⁷⁸ A randomized controlled trial in 111 healthy older subjects found 250 mg per day of grape extract improved scores on cognitive tests after 12 weeks.²⁷⁹ Older adults with cognitive decline and mild cognitive impairment experienced improved cognitive performance after drinking 15‒20 ounces (depending on weight) per day of Concord grape juice for 12–16 weeks in small controlled trials.^280,281 In a small placebo-controlled trial of 10 participants with mild cognitive decline, those receiving placebo exhibited significant diminishment in metabolic activity in regions of the brain involved in dementia, but those receiving grape extract had no such decline.²⁸² A randomized controlled trial in 215 healthy older adults identified a significant effect of a high-polyphenol grape plus blueberry extract, taken at a dose of 600 mg daily for six months, in those with the lowest cognitive test scores at baseline.²⁸³

Resveratrol. Resveratrol is a grape polyphenol found especially in red wine and shown in numerous studies to have powerful free radical-quenching capacity.²⁸⁴ Resveratrol appears to slow cognitive decline through regulating age-related signaling, improving cerebral blood flow, and increasing neuroplasticity.²⁸⁵ Findings from clinical trials have been mixed; however, a meta-analysis that included 10 randomized controlled trials found resveratrol may improve some aspects of cognitive function and mood in older individuals.²⁸⁶

In a randomized placebo-controlled trial in 46 healthy individuals aged 50‒75 years, 26 weeks of treatment with 200 mg resveratrol daily led to better performance on memory tasks, as well as improved glucose metabolism (indicated by lower hemoglobin A1C [HbA1c]), increased neuronal connectivity, and decreased body fat.²⁸⁷ Another trial in 40 patients with mild cognitive impairment found 26 weeks of treatment with 200 mg resveratrol daily resulted in better glucose metabolism and better preservation of brain structure, but no difference in cognitive function compared with placebo.²⁸⁸ In a controlled trial in sedentary, overweight, older adults, 1,000 mg resveratrol daily improved psychomotor speed, but not other aspects of cognitive function, after 90 days, while 300 mg daily had no effect.²⁸⁹ In a controlled trial in postmenopausal women, 150 mg resveratrol daily improved cerebrovascular function and cognitive performance after 14 weeks; the investigators proposed that some of resveratrol’s effects in this population were due to its phytoestrogenic actions.²⁹⁰

Green tea catechins. Green tea is a source of polyphenolic catechins. A growing body of evidence suggests green tea catechins may slow brain aging by modulating neural growth factors, regulating cell signaling involved in inflammation and neuronal survival, and reducing accumulation of abnormal proteins.^291,292 A review of 21 studies found green tea may reduce anxiety, benefit memory and attention, and enhance brain function.²⁹³

Chlorogenic acids. Chlorogenic acids are polyphenols found in coffee, and many studies have linked chlorogenic acid consumption to better cognitive function and mood.²⁹⁴ In 38 healthy adults aged 50–69 years with subjective memory complaints, drinking a beverage providing 300 mg chlorogenic acid at bedtime for 16 weeks resulted in better cognitive performance and improved blood levels of proteins thought to be markers of early Alzheimer disease.²⁹⁵

Melatonin

Melatonin helps regulate the circadian control center of the brain and promotes sleep. Circadian patterns and nighttime melatonin production diminish with age, contributing to poor sleep and consequent neurodegeneration.^296,297 In older individuals, lower nighttime melatonin levels have been correlated with mild cognitive impairment and dementia.^298-300 Animal studies suggest melatonin can repair circadian and sleep disturbance and reduce associated cognitive problems.^301-303 Melatonin’s potential to reduce neuroinflammation and neurodegeneration have also been noted in animal models of both Alzheimer and vascular dementia.^304-306

In a retrospective analysis of patients with mild cognitive impairment, the effect of melatonin on sleep, mood, and several tests of cognitive function was reported. The analysis compared the effects of standard medication with or without the addition of melatonin in doses of 3‒24 mg at bedtime on a total of 96 outpatients. Participants were monitored for 15–60 months, and results showed the melatonin-treated group had improved sleep, mood, and performed better on all tests of cognitive function.³⁰⁷ In a similarly designed retrospective analysis that was previously conducted by these researchers, 9–18 months of treatment with 3–9 mg melatonin nightly improved performance on all but one cognitive test in patients with mild cognitive impairment.³⁰⁸

A randomized controlled trial in 139 elderly participants undergoing hip joint surgery found 1 mg melatonin taken before bedtime for six days beginning one day before surgery prevented postoperative cognitive decline; there were also improvements in sleep quality, fatigue, and general well-being compared with placebo.³¹⁰ Clinical trials in Alzheimer disease patients indicate melatonin may improve sleep, reduce behavioral symptoms, and enhance some aspects of cognitive function.^311,312

In a first-of-its-kind study, melatonin’s effect on memory was compared with two of its metabolites (N1-acetyl-N2-formyl-5-methoxykynuramine [AFMK] and N1-acetyl-5-methoxykynuramine [AMK]).³⁰⁹ The study tested the interventions on mice using a novel object recognition task and an analysis of melatonin and its metabolites in specific brain regions involved in cognitive memory. It is important to note that the novel object recognition task is used on mice because they have an instinctive tendency to examine unfamiliar objects. The results showed melatonin and its metabolites produced notable improvements in object recognition compared with controls. The most potent effect was observed in old mice that received the metabolite AMK, as these mice indicated recognition of objects for up to four days. The study also showed melatonin can accumulate along with its metabolites in the hippocampus and the neighboring perirhinal cortex, which is involved in visual recognition.

Omega-3 Fatty Acids & Fish Oil

The long-chain omega-3 fatty acid docosahexaenoic acid (DHA) is a critical nutrient for brain health, and deficiency can cause symptoms such as poor mood and cognitive dysfunction. DHA is found in high concentrations in neuronal cell membranes where it plays an important structural role in maintaining membrane fluidity.^313,314 Preclinical research showed DHA plus eicosapentaenoic acid (EPA), another omega-3 fatty acid from fish, may protect against amyloid plaques and neurofibrillary tangles,³¹⁵ as well as prevent blockages and improve blood flow in small vessels in the brain.³¹⁶ Adequate omega-3 fatty acid status may also be needed for proper use of B vitamins in the brain.^314,317 In addition, DHA has anti-inflammatory effects and is a precursor for neuroprotectin D1, a signaling molecule involved in neuronal growth and survival.³¹³

A number of studies have noted a strong association between higher seafood intake, or higher blood or dietary levels of omega-3 fatty acids, and better cognitive function.^318-320 One study in 2,622 older adults found those with the highest blood levels of long-chain omega-3 fatty acids (including EPA and DHA) had an 18% lower risk of unhealthy aging, defined as chronic disease, physical or cognitive dysfunction, or death for any reason, over a 13-year period.³²¹ Results from other research indicate the ratio of omega-6 to omega-3 fatty acids may be an important factor affecting brain structure and cognitive function.^322,323

A meta-analysis of six randomized controlled trials using doses ranging from 400 to 1,800 mg daily of combined omega-3 fatty acids for periods of 3–40 months found that omega-3 fatty acid supplements can slow the rate of cognitive decline in the elderly.³²⁴ Similarly, a large review of 24 studies found evidence suggesting a beneficial effect of omega-3 fatty acid intake on cognitive aging.³²⁵ However, findings have been inconsistent. For example, 1,720 mg DHA and 600 mg EPA daily for 18 months had no effect on cognitive decline in 390 healthy older subjects³²⁶; and, in 99 participants with normal or mildly impaired cognitive function, 750 mg DHA plus 120 mg EPA daily for one year also showed no significant effects.³²⁷

In a randomized placebo-controlled trial, 1,680 participants aged 70 and over with subjective memory complaints received either 800 mg DHA plus 225 mg EPA daily or placebo for three years. Although DHA plus EPA supplementation did not affect cognitive function in the initial analysis,³²⁸ a secondary analysis including only those with a low baseline omega-3 index (a measure of omega-3 fatty acids in red blood cells) showed supplementation led to improved executive function in this group.³²⁹ Data from the same study suggest those with an omega-3 index of ≤ 5% have increased odds of cognitive decline and may benefit most from supplementation.³³⁰

Another factor that may influence clinical trial results is the presence of the apolipoprotein E4 (ApoE4) gene variant, which is associated with disrupted DHA metabolism.³³¹ The ApoE4 variant is associated with an increased risk of dementia in individuals with cognitive impairment.⁵⁵² One study in 915 elderly participants only noted a link between higher seafood consumption and reduced cognitive decline in ApoE4 carriers.³³² In another study, an observed protective effect of seafood consumption against amyloid plaques and neurofibrillary tangles was found to be due solely to an effect in ApoE4 carriers.³¹⁵ Because of such findings, it has been proposed that DHA supplementation may be more important in carriers of ApoE4.³³³

B Vitamins

B vitamins are needed for homocysteine metabolism, and lower levels of B vitamins, particularly folate, B12, and B6, have been correlated with high homocysteine levels and greater cognitive decline in the elderly.^334-337 While B vitamin supplementation has been shown to effectively lower high homocysteine levels, so far, results from clinical trials have been mixed with regard to cognitive benefits.^338-341

Researchers have been investigating factors that identify those most likely to benefit from treatment with B vitamins, such as omega-3 fatty acid status, homocysteine level, or degree of cognitive impairment. One randomized trial found the positive effect of B vitamin supplementation on cognitive function was dependent on sufficient omega-3 fatty acid status.³¹⁷ A 2-year randomized controlled trial found supplementing with B6, B12, and folic acid slowed cognitive decline only in those whose baseline homocysteine levels were 11.3 mmol/L or higher.³⁴² Supplementing with folic acid plus B12 was associated with reduced risk of dementia during five years of monitoring in older adults with mild cognitive impairment.³⁴³ In older adults diagnosed with mild cognitive impairment, 400 mcg folic acid daily reduced cognitive decline and decreased blood levels of inflammatory cytokines after six months³⁴⁴ and one year.³⁴⁵ Even after only 12 weeks, a supplement with B6, folic acid, and B12 decreased homocysteine levels and improved cognitive function and depression in a trial of participants with mild cognitive impairment.³⁴⁶

Another potentially important factor is the effect of the methylenetetrahydrofolate reductase (MTHFR) gene; carriers of a particular MTHFR variant have abnormal folate metabolism and require higher intake of folic acid to avoid deficiency.³⁴⁷ They may also benefit less from ordinary folic acid supplements. To overcome this obstacle, one preliminary study used a supplement with L-methylfolate (active form of folate) and B12 (methylcobalamin) in patients with high homocysteine levels and found this treatment reduced cognitive decline and was more effective in those with milder, versus more severe, cognitive dysfunction.³⁴⁸

Alpha-Glyceryl Phosphoryl Choline (Choline Alphoscerate)

Alpha-glyceryl phosphoryl choline (α-GPC) (also known as choline alphoscerate) is a semisynthetic derivative of the nutrient phosphatidylcholine and precursor to the neurotransmitter acetylcholine.³⁴⁹ Acetylcholine is a major neurotransmitter in the autonomic nervous system, and its accelerated breakdown is thought to contribute to age-related cognitive decline and dementia. In fact, reduced concentration of the acetylcholine-metabolizing enzyme, acetylcholinesterase, has been observed in brains of “super agers” (ie, elderly individuals with unusually youthful cognitive function).²⁴⁴

Acetylcholine precursors, alone or in conjunction with acetylcholinesterase inhibitor drugs, are a promising approach to dementia treatment.^349-351 One randomized controlled trial compared the effects of 1,200 mg α-GPC daily for 180 days to placebo in 261 patients with mild-to-moderate Alzheimer disease. Those receiving α-GPC experienced improvements in cognitive function and behavioral assessments, while those receiving placebo experienced no change or worsening of clinical measures.³⁵² In a preliminary trial in 50 subjects with mild cognitive impairment, 1,200 mg α-GPC per day for three months resulted in improved cognitive function. A follow-up evaluation performed seven to nine months after the end of treatment found cognitive function remained at a higher level than before treatment.³⁵³ Another pilot trial found α-GPC had beneficial effects on cognitive function after 15 days of treatment in patients who had experienced stroke.³⁵⁴

Reports from an ongoing randomized controlled trial showed combination treatment with the acetylcholinesterase inhibitor donepezil plus α-GPC was more effective than donepezil plus placebo in preserving cognitive and behavioral function in patients with Alzheimer disease and cerebrovascular injury after one³⁵⁵ and two years,³⁵⁶ and reduced apathy, the loss of motivation associated with progressive dementia, after three years.³⁵⁷ The most recent report from this trial showed co-treatment with these two agents reduced Alzheimer-related behavior and mood disorders.³⁵⁸

Mango Leaf Extract

Leaves from the mango plant (Mangifera indica) have been used in traditional medicine practices for general health and as a remedy for fatigue.⁵⁵³ Extracts from mango leaf have been shown to have anti-inflammatory and neuroprotective properties in preclinical studies; these positive effects are thought to be attributable largely to mangiferin, a major polyphenol in mango leaf extract.^554-556 Mangiferin appears to act as an inhibitor of catechol-O-methyltransferase (COMT), an enzyme responsible for breaking down neurotransmitters such as dopamine, epinephrine, and norepinephrine.^553,557 Animal studies have shown that mangiferin improves several aspects of cognition, including spatial recognition and short- and long-term memory.⁵⁵⁸

In two small, randomized, double-blind, placebo-controlled crossover trials, a single 500 mg dose of mango leaf extract standardized to 60% mangiferin was shown to improve reaction time by nearly 5% compared with placebo and lessen fatigue by nearly 50% compared to baseline.⁵⁵³ In another randomized, double-blind, placebo-controlled, crossover study with 70 healthy adults, a single 300 mg dose of the same mango leaf extract significantly improved performance accuracy (2.4%), episodic memory (2.8%), and visual information processing scores compared with placebo over the course of several hours.⁵⁵⁴

Peppermint

Extracts and essential oils of peppermint (Mentha piperita) are rich in monoterpenes, which are known for their cognitive benefits.^559,560 Peppermint essential oil has been shown to inhibit acetylcholinesterase (AChE) and bind to GABA_A and nicotinic receptors. In a small clinical study, 100 µL of peppermint essential oil improved performance on a cognitively demanding task and prevented cognitive fatigue up to several hours after the dose.⁵⁶⁰

Phosphatidylserine

The brain has a high concentration of phosphatidylserine, a phospholipid that incorporates two fatty acids and is part of cell membranes and myelin. Phosphatidylserine is necessary for all aspects of cognitive function, as well as nervous system control over motor function. Aging is associated with deterioration of brain structure and chemistry that can be affected by phosphatidylserine supplementation.^359,360

Early clinical trials using phosphatidylserine extracted from bovine brain tissue showed promising cognitive benefits in elderly individuals^361,362; however, safety issues concerning this source of phosphatidylserine led to its removal from the market. Phosphatidylserine can also be extracted from soybeans. Soybean phosphatidylserine, at a dose of 300 mg per day, has been shown in uncontrolled trials to improve cognitive performance in some older individuals with memory complaints.^363,364

Bovine phosphatidylserine differs from soybean phosphatidylserine in its fatty acid profile: bovine-sourced contains the omega-3 fatty acid DHA, while soybean-sourced does not. A marine-sourced phosphatidylserine complexed with the omega-3 fatty acids EPA and DHA has been shown to be safe and may have positive effects on cognition in older adults.³⁶⁵ In an open trial in eight volunteers 60 years of age and older with subjective memory complaints, 300 mg per day phosphatidylserine with EPA and DHA for six weeks led to improved performance on a short-term memory test.³⁶⁶ A randomized controlled trial in 157 participants with subjective memory complaints compared the effects of 300 mg marine phosphatidylserine daily with placebo. At the end of 15 weeks, those receiving phosphatidylserine performed better on a test of short-term memory, and the effect was strongest in those with the best baseline cognitive function.³⁶⁷ The trial continued for another 15 weeks with all participants receiving 100 mg phosphatidylserine daily; those who had already been receiving the supplement maintained their cognitive gains and those who had been receiving placebo showed improved cognitive function.³⁶⁰

Colostrinin (Proline-rich Polypeptide Complex)

Colostrum, the first milk produced by the breasts after childbirth, is well known for its high levels of antibodies and other factors with immune-activating effects.^368,369 Findings from preclinical and clinical studies suggest colostrinin, a proline-rich polypeptide complex found in colostrum, may help prevent the progression of cognitive decline, particularly in people with Alzheimer disease.^370,371 A number of studies have found a range of possible mechanisms for colostrinin’s beneficial effects, including modulating immune activity, preventing oxidative stress and oxidative damage to DNA, reducing inflammation, inhibiting overproduction of nitric oxide, and decreasing age-related mitochondrial dysfunction.^372-376

A randomized controlled trial compared colostrinin to placebo in 105 subjects with mild-to-moderate Alzheimer disease. The colostrinin group received 100 mcg 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 weeks, following the same dosing regimen. Colostrinin treatment had a stabilizing effect on cognitive function and ability to perform activities of daily living, and participants with mild cognitive losses responded better to treatment than those with more advanced losses.³⁷⁷ Another trial used the same dosing schedule for 16 to 28 months in 33 Alzheimer disease patients and found it resulted in stabilization or improvement in health status.³⁷⁸ In an earlier clinical trial including 46 patients with mild-to-moderate Alzheimer disease, participants were assigned to receive either 100 mcg colostrinin, 100 mcg selenium, or placebo in 3-week cycles, followed by two weeks without treatment, for one year. Eight of the 15 patients treated with colostrinin experienced improvement, and the other seven had no change in their condition; in contrast, none of the patients in the selenium or placebo groups improved, and some worsened.³⁷⁹ Studies have reported mild side effects that resolve quickly in some patients treated with colostrinin.^378,379

Vinpocetine

Vinpocetine, also known as Cavinton, is a synthetic derivative of an alkaloid from periwinkle (Vinca minor). Vinpocetine has demonstrated neuroprotective effects such as altering inflammatory signaling, reducing oxidative stress, improving cellular energy production, inhibiting thickening of blood vessel walls, dilating cerebral blood vessels, and possibly preventing atherosclerotic plaque formation.^380-383

In a placebo-controlled trial in 26 patients who had experienced multiple strokes, vinpocetine prevented deterioration on one test of cognitive function after three months.³⁸⁴ Other studies using oral vinpocetine have noted its ability to improve cognitive performance in patients with mild cognitive impairment as well as cerebrovascular insufficiency.^385,386 Note: women who are pregnant or could become pregnant should not use vinpocetine.

Lithium

Lithium is a mineral used in high doses as a mood stabilizer, primarily in patients with bipolar disorder.^387,388 Lithium is naturally present in trace amounts in drinking water, and higher occurrence of lithium in drinking water has been correlated with lower rates of dementia and psychiatric disorders in population studies.^389,390 A growing body of preclinical evidence suggests lithium may have neuroprotective effects through its abilities to prevent oxidative and inflammatory neuronal damage, enhance neuroplasticity, modulate protein metabolism, and regulate circadian rhythms and hypothalamic-pituitary-adrenal (HPA) axis activity.^{387,388,391-393} In addition, animal and laboratory research suggests chronic low-dose lithium treatment can increase neuronal production of BDNF.^394-396

A meta-analysis of three clinical trials including a combined total of 222 subjects concluded lithium therapy may be beneficial in individuals with mild cognitive impairment and Alzheimer disease.³⁹⁷ Because of lithium’s substantial potential for toxicity in higher doses,³⁸⁸ microdose therapy is especially appealing. In one trial, Alzheimer disease patients treated with lithium, at a microdose of 300 mcg daily, had less cognitive decline than untreated patients. The difference in cognitive function was significant after three months and progressively widened during the course of the 15-month trial.³⁹⁸ Microdose lithium has been shown in rats predisposed to Alzheimer-like pathology to reduce oxidative stress, neuroinflammation, and abnormal protein accumulation, as well as promote neuronal regeneration and prevent memory loss.^399,400 Preclinical research has shown lithium orotate, the form of lithium used in dietary supplements, has a high level of safety.⁵⁶¹

Cocoa

Cocoa is made from the seeds of the cocoa tree, Theobroma cacao. Cocoa has high concentrations of free radical-quenching polyphenols called flavanols. Mounting evidence suggests cocoa and its flavanols can improve vascular function, promote cerebrovascular blood flow, and strengthen cognitive function.^401,402 Findings from a laboratory study suggest cocoa may also inhibit aggregation of β-amyloid.⁴⁰³ In addition, cocoa’s caffeine, catechins, and other constituents may contribute to its benefits on brain health.⁴⁰⁴ In general, chocolate products contain polyphenols in proportion to their cocoa content; darker chocolate contains more beneficial compounds than lighter or “milk” chocolate.

Examining data from 2,056 participants in the Seniors-Study on Nutrition and Cardiovascular Risk in Spain, researchers noted daily consumption of 10 grams (0.35 ounces, roughly a one inch square piece) or more of dark chocolate in the previous year was associated with better cognitive performance and lower risk of mild cognitive impairment compared with not eating dark chocolate.⁴⁰⁵ Another study in 531 subjects, aged 65 years and older, found chocolate consumption was correlated with a reduced risk of cognitive decline during approximately four years of monitoring in those with low caffeine intake (less than 75 mg per day; roughly the amount in a 6-ounce cup of coffee or two cups of tea).⁴⁰⁶

In a randomized controlled trial in 40 healthy older individuals, taking a cocoa drink providing 494 mg flavanols once daily for 12 weeks increased blood levels of BDNF and improved cognitive function.⁴⁰⁷ An eight-week randomized controlled trial compared the effects of supplemental drinks providing different amounts of cocoa flavanols in 90 elderly subjects without clinical evidence of cognitive dysfunction. At the end of the trial, cognitive performance on some tests improved in those receiving 993 mg cocoa flavanols per day compared with lower amounts. In addition, those receiving 993 mg and 520 mg had improvements in insulin resistance, blood pressure, and lipid peroxidation (a measure of oxidative stress) compared with those receiving 48 mg per day.⁴⁰⁸ In a three-month randomized controlled trial in healthy older adults, eating a high-cocoa diet improved regional brain function as well as cognitive performance.⁴⁰⁹

Spearmint Extract

Spearmint (Mentha spicata) is an aromatic herb that is rich in water-soluble polyphenols, many of which have anti-inflammatory and free radical-reducing properties. Rosmarinic acid and its derivatives generally make up the greatest proportion of spearmint’s polyphenols.⁴¹⁰

Rosmarinic acid has shown neuroprotective effects, such as reducing neuroinflammation and brain oxidative stress and preventing β-amyloid-induced cognitive decline, in laboratory models. ^411,412 Rosmarinic acid also appears to inhibit an enzyme involved in tau protein pathology, which studies suggest plays a role in cognitive decline.⁴¹³ In addition, spearmint extract has been found to inhibit the enzyme acetylcholinesterase, an action that may increase levels of acetylcholine and thereby support learning, memory, and mood.⁴¹⁰

In a randomized placebo-controlled trial, 90 individuals with age-related memory impairment received either a high-rosmarinic acid spearmint extract (900 mg dose or 600 mg dose) or placebo daily for 90 days. Those receiving the 900 mg dose performed better on memory tests and reported improved ability to fall asleep compared with placebo.⁴¹⁴ In a pilot trial in 11 subjects with self-reported mild memory impairment, 30 days of treatment with 900 mg of a high-rosmarinic acid spearmint extract daily resulted in improved performance on tests of reasoning, attention, and concentration. Even short-term administration resulted in improvements in attention and concentration that were noted within 2–4 hours.⁴¹⁵

Green Oat Extract

Oat (Avena sativa) is a cereal grain with many active compounds.^416,417 An extract from wild green oat has been shown to inhibit an enzyme called monoamine oxidase-B (MAO-B).⁴¹⁶ The activity of MAO-B, which metabolizes dopamine, increases in older age, lowering dopamine levels and possibly driving oxidative stress and mitochondrial dysfunction and accelerating tissue aging.^418,419 Blocking MAO-B helps normalize dopamine levels, which may reduce oxidative stress and improve aspects of cognition and memory.^419,420 Wild green oat extract has also been found to dilate cerebral blood vessels and inhibit another enzyme called phosphodiesterase-4,⁴²¹ an effect that may slow age-related cognitive decline.^422,423

In healthy adults, 1,500 mg of wild green oat extract increased arterial blood flow by slightly more than 40% compared with placebo.⁴²⁴ In healthy middle-aged adults, a single 800 mg dose of wild green oat extract improved performance on tests of attention, delayed recall, memory, and executive function.⁴²⁵ In patients with mild age-related cognitive problems, 1,600 mg wild green oat extract improved performance on a test measuring attention, concentration, and ability to focus on a task.⁴²⁶

Lion’s Mane

Lion’s mane (Hericium erinaceus) is a mushroom with a long history of medicinal use in traditional Chinese medicine. Extracts have been shown to have anti-inflammatory and oxidative stress-reducing effects, and consumption of Lion’s mane has been reported to be associated with neuroprotective, pro-cognitive, anti-aging, and antidepressant properties, among other health benefits.⁴²⁷ In a randomized controlled trial in 30 older individuals with mild cognitive impairment, daily treatment with 3,000 mg powdered lion’s mane for 16 weeks resulted in improved cognitive function relative to placebo.⁴²⁸ In animal research, lion’s mane enhanced neuronal function and improved memory performance in healthy wild-type mice.⁴²⁹ Extracts of lion’s mane have also been found to stimulate neuronal growth factor and formation of new neurons, as well as decrease β-amyloid plaque and amyloid-induced inflammation, in mouse models of Alzheimer disease.^430,431

Magnesium-L-threonate

Magnesium-L-threonate is a form of magnesium found to be particularly effective in raising brain magnesium levels.^258,259 Increasing brain magnesium levels enhanced neuroplasticity and improved cognitive function in research animals.^258,260 Supplementation with magnesium-L-threonate has been shown to prevent age-related decrease of a specific neurotransmitter receptor (NMDA receptor subunit NR2B), inhibit inflammatory signaling, reduce amyloid plaque formation, preserve neural connections, and protect against memory loss in animal models of aging and Alzheimer disease.^259,261-263 Other animal research suggests magnesium-L-threonate may augment the cognitive-boosting effects of mentally and physically stimulating activity in mice with Alzheimer-like brain pathology.²⁶⁴

Pyrroloquinoline Quinone

Pyrroloquinoline quinone, or PQQ, is a vital compound that supports growth and development.⁴³² PQQ plays a critical role in oxidation-reduction (or redox) biochemical reactions, in which electrons are given by donor molecules and taken up by recipient molecules. Redox reactions are fundamental to virtually all cellular processes.^432,433 Preclinical research suggests boosting PQQ levels may improve mitochondrial numbers and function, reduce systemic and brain inflammation, increase cell longevity, protect against neurotoxins, and possibly improve neurological and cardiovascular health.^{433,434,435-439} A number of studies also show PQQ may prevent the accumulation of β-amyloid.^440-443 Furthermore, PQQ has been found to stimulate the production of a protein called nerve growth factor,^444-446 promote regeneration of nerve cells,^447,448 and preserve cognitive function in laboratory animals.⁴⁴⁹

Research findings suggest PQQ may improve cognitive function by increasing regional brain blood flow and oxygen use. In a controlled trial in 41 healthy elderly subjects, 20 mg PQQ daily for 12 weeks resulted in increased cerebral blood flow and slower decline in cognitive performance compared with placebo. In addition, participants with the lowest cognitive function at the beginning of the trial exhibited improvement in one aspect of cognitive function at the end of the trial.⁴⁵⁰ Another study similarly noted that taking 20 mg PQQ daily for 12 weeks increased regional brain blood flow and oxygen utilization in healthy subjects.⁴⁵¹

Nicotinamide Riboside

Nicotinamide riboside is a form of vitamin B3. Like other forms of B3 (nicotinamide and nicotinic acid), nicotinamide riboside is a precursor to nicotinamide adenine dinucleotide (NAD⁺) in the body.^452,453 NAD⁺ is a universal cofactor that plays a critical role in redox biochemical reactions, through which it is converted to its reduced form, NADH. In addition, NAD⁺ appears to participate in regulating enzymes that govern an array of cell functions, including gene expression, metabolism, DNA repair, apoptosis (programmed cell death), and aging.^454-456

Aging is associated with decreased NAD⁺ production, and a decreased NAD⁺/NADH ratio has been correlated with mitochondrial dysfunction and age-related and metabolic disorders such as cognitive decline and dementia, diabetes, obesity, non-alcoholic fatty liver disease, cardiovascular disease, and some cancers.^452,457-459 It is thought that raising NAD⁺ availability may contribute to slowing the aging process and preventing age-related diseases.^457,460

In healthy elderly volunteers, 250 mg per day and 500 mg per day of the NAD ⁺ precursor nicotinamide riboside safely and dose-dependently raised blood levels of NAD⁺ after four weeks.⁴⁶¹ In mice, administering oral nicotinamide riboside has been found to increase cerebral NAD⁺ levels and improve cognitive function,⁴⁶² enhance neuroplasticity, and reduce tau protein-induced neuronal damage.⁴⁶³ In a rat model of vascular dementia, intraperitoneal injection of NAD⁺ was shown to ameliorate cognitive deficits and inhibit neuroinflammation by protecting mitochondria from damage and decreasing reactive oxygen species production.⁵⁶² Decreased gene expression of PPAR-γ co-activator 1α (PGC-1α), in addition to its upstream transcription factor Sirt1, is thought to contribute to this cognitive impairment, where NAD⁺ administration reversed this decrease. Further evidence from animal studies suggest NAD⁺ therapy could possibly stimulate mitochondrial activity, maintain the regenerative potential of stem cells, and extend lifespan.^464,465

In an in vitro study employing a microglial cell line, NAD ⁺ displayed protective effects against inflammation, mitochondrial damage, and reactive oxygen species production. Further, Sirt1 overexpression mimicked the protective effects of NAD⁺.⁵⁶²

Coenzyme Q10

Coenzyme Q10 (CoQ10) plays an essential role in mitochondrial energy production. CoQ10 has demonstrated neuroprotective effects that may be mediated through enhanced mitochondrial function and modulation of microglial cells, the brain’s immune cells that mediate neuroinflammation.^466,467 Lower blood levels of CoQ10 have been correlated with increased risk of disabling dementia in older individuals⁴⁶⁸ and worse cognitive function in heart failure patients.⁴⁶⁹ Preclinical evidence suggest CoQ10 may slow cognitive decline in patients with neurodegenerative diseases like Huntington, Parkinson, and Alzheimer disease.^470-472 Long-term consumption (1 to 2 years) of 100–150 mg ubiquinol (the reduced form of CoQ10) daily has been shown to improve a marker of cognitive performance in Japanese individuals of a broad age range.⁵⁶³

Ashwagandha

Withania somnifera, more commonly known as ashwagandha, is a plant that has been used in Ayurvedic medicine for centuries. The plant and root extracts of ashwagandha contain several bioactive compounds with antioxidant, anti-inflammatory, and immune-stimulating properties.⁴⁷³ Cellular and animal models show that ashwagandha extracts and related compounds rescue neuronal cells from chemical damage and inflammation through multiple signaling pathways, protecting neurons from neurodegenerative processes that typify conditions including Alzheimer, Parkinson, and Huntington diseases.⁴⁷⁴

In human studies, ashwagandha extract has also been shown to improve memory and cognitive function. In a double-blind placebo-controlled study, 50 adults were randomly assigned to receive either ashwagandha root extract (300 mg twice daily) or placebo for eight weeks. Ashwagandha was associated with statistically significant improvements in short-term and general memory, executive function, sustained attention, and information-processing speed.⁴⁷⁵ Furthermore, in a randomized controlled trial of 53 people with bipolar disorder, adjunctive use of 500 mg per day of ashwagandha extract resulted in improvements in auditory-verbal working memory, reaction time, and social cognition.⁴⁷⁶

One of the active compounds found in ashwagandha extract is withanone. Administration of withanone to rats for three weeks was shown to significantly improve cognitive skills by decreasing levels of inflammatory molecules. In the same study, withanone was shown to inhibit β-amyloid, a protein implicated in the development of Alzheimer disease.⁴⁷⁹

Pregnenolone

Pregnenolone is a steroid hormone that is synthesized from cholesterol in the brain, adrenal glands, and other organs. Pregnenolone can either modulate signaling pathways itself or undergo further metabolism to form other steroid hormones, including progesterone, aldosterone, cortisol, and testosterone.⁴⁸⁰ In the brain, pregnenolone has been shown to modulate NMDA receptor-mediated neurotransmission, which supports learning and memory.^481,564 Furthermore, pregnenolone has anti-inflammatory properties.⁴⁸²

In rats presented with learning and memory challenges, intranasal pregnenolone administration resulted in improvements in learning, long-term memory, and resistance to memory extinction.⁴⁸³ Intraperitoneal injection of 10 mg/kg pregnenolone was shown to ameliorate cognitive impairments induced by NMDA receptor antagonism in rats.⁵⁶⁵ In a preliminary study, aged rats were shown to have significantly reduced levels of pregnenolone in the hippocampus and other brain regions, and animals with less memory problems had higher concentrations of pregnenolone. Memory deficit in these animals was temporarily corrected by pregnenolone injection.⁴⁸⁴

Most human studies of the effects of pregnenolone on cognitive decline have been performed in the context of psychiatric disorders, such as schizophrenia and bipolar disorder. In an 8-week, randomized, placebo-controlled trial in patients with recent-onset schizophrenia or a related disorder, use of adjunctive pregnenolone, taken orally, at a dose of 50 mg/day was shown to result in a significant improvement in executive functions as well as visual and sustained attention.⁴⁸⁵ Another placebo-controlled study in patients with schizophrenia found 30 mg/day pregnenolone improved attention and working memory performance.⁴⁸⁶

Sage

Sage (Salvia officinalis), a perennial bush native to the Mediterranean region, has been used for its medicinal (and culinary) properties since ancient times. More recently, sage has drawn attention for its cognitive-enhancing abilities.⁵⁶⁶ Sage extracts have been shown in animal models of Alzheimer to inhibit acetylcholinesterase activity and prevent decline in peripheral BDNF levels,^567,568 which tend to be reduced in people with Alzheimer or mild cognitive impairment.⁵⁶⁹ Extracts and bioactive compounds from sage have also been shown to have some anti-inflammatory effects.⁵⁶⁶

In a placebo-controlled trial in patients with mild-to-moderate Alzheimer disease, those treated with sage extract for 16 weeks scored better on two different standardized assessments of cognitive function compared with those treated with placebo.⁵⁷⁰ In another randomized placebo-controlled trial, a standardized extract of sage at doses ranging from 167 mg to 1,332 mg was given to 20 participants aged 65 and older. The participants took single doses separated by 7-day washout periods. The 333 mg dose improved accuracy of attention and certain aspects of memory for up to six hours post-treatment compared with placebo.⁵⁷¹ In an acute, double-blind, placebo-controlled study in healthy young adults aged 18‒25, 150 and 300 mg of a commercial sage extract improved memory performance compared with placebo.⁵⁷²

Dried sage leaf was also shown to improve mood and cognitive performance in healthy young volunteers.⁵⁷³ A systematic review concluded that sage preparations may help enhance cognitive performance in healthy subjects and in patients with dementia; however, further rigorous trials are needed.⁵⁷⁴

Gotu kola

Gotu kola (Centella asiatica), a leafy green plant historically used in traditional medicine in Southeast Asia, is valued for its high concentrations of several beneficial nutrients, including triterpenoids, carotenoids, vitamins B and C, minerals, and other phytonutrients.⁴⁸⁸ One key active ingredient found in gotu kola is asiatic acid, a triterpene that preclinical studies suggest may prevent cognitive decline caused by some drugs and also modulate neurotransmission, among other beneficial cognitive and neural effects.^489-492 Many gotu kola preparations are standardized to asiaticosides, which are metabolized to asiatic acid in the body.⁴⁹³

Preclinical studies have shown gotu kola can reduce markers of oxidative stress, which may in turn improve neuronal health.^494-496 Furthermore, gotu kola has been shown to decrease acetylcholinesterase levels in the hippocampus and cerebral cortex of rats at a rate comparable with donepezil, a pharmacologic acetylcholinesterase inhibitor.^495,497

In a mouse model of Alzheimer disease, gotu kola water extract was shown to improve memory in a dose-dependent manner. Furthermore, markers of neural density were increased in brain regions that influence information processing (ie, the hippocampus and prefrontal cortex).⁴⁹⁴ Among older mice, gotu kola water extract was shown to improve performance on a test that measures spatial learning and memory.⁴⁹⁸

In a study of 28 healthy elderly volunteers, 250–750 mg gotu kola extract daily for two months improved working memory and self-rated mood.⁴⁹⁹ In a systematic review and meta-analysis of randomized controlled trials in humans, researchers reported that the gotu kola products did not significantly improve cognitive function domains compared with placebo; however, gotu kola did improve mood and alertness, and no adverse events were reported.⁵⁰⁰

Carotenoids

Carotenoids are organic, strongly pigmented compounds found in algae, plants, fungi, and many bacteria. Carotenoids can be classified as xanthophylls (eg, lutein and zeaxanthin) or carotenes (eg, β-carotene and lycopene). About 50 different types of carotenoids have been found in fruits and vegetables consumed by humans, and about 20 carotenoids are found in human tissues and blood.⁵⁰¹

Higher serum and retinal concentrations of lutein and zeaxanthin have been associated with improvements in several biomarkers of inflammation and measures of cognition and neurotransmission.⁵⁰¹ Neuroimaging studies revealed that older adults with higher concentrations of lutein and zeaxanthin had increased white matter integrity, particularly in brain regions that are vulnerable to age-related changes.⁵⁰² Carotenoids have also been shown to reduce inflammatory signaling by decreasing circulating levels of cytokines and other proinflammatory molecules. Furthermore, carotenoids protect cells from oxidative stress, thereby possibly slowing cognitive decline by preventing neuronal cell damage.⁵⁰¹

There is extensive evidence supporting the role of carotenoids in cognitive performance. Based on results of the 2011‒2014 National Health and Nutrition Examination Survey (NHANES), higher dietary intake of lutein and zeaxanthin was associated with better scores on all learning and memory tests in participants 60 years and older, suggesting lutein and zeaxanthin may help prevent or slow age-related cognitive decline.⁵⁰³ In contrast, low intake of carotene, among other nutrients, was significantly correlated with an increased risk for cognitive decline in an elderly population.⁵⁰⁴ Another observational study followed over 7,000 participants who were at least 45 years old at baseline for an average of 16 years. Total serum lutein and zeaxanthin concentration at baseline was associated with a reduced risk of developing all-cause dementia—each 15.4 μg/dL increase in lutein and zeaxanthin corresponded with a 7% decrease in risk in those 65 years or older. Serum β-cryptoxanthin at baseline was associated with a 14% decreased risk of dementia for each 8.6 μg/dL increase in both age groups (45+ and 65+).⁶⁰⁹ Furthermore, higher serum and retinal concentrations of lutein and zeaxanthin have been associated with improved visual-spatial processing and decision making. During processing and decision-making tasks, functional MRI (fMRI) showed improved neural efficiency in participants who performed better on tasks and who had higher levels of lutein and zeaxanthin.⁵⁰⁵ Finally, the effects of dietary carotenoids were assessed in nearly 50,000 female nurses. Self-reported subjective cognitive function, assessed in 2012 through 2014, was significantly associated with dietary carotenoid consumption during the prior three decades (1984 through 2006). Nurses who consumed the lowest amounts of carotenoids had 33% higher risk of poor cognitive function than those who consumed the highest amounts.⁵⁰⁶

In a randomized controlled trial, 80 adults aged 65 to 92 years received either 12 mg lutein and zeaxanthin or placebo for 12 months. Neurons in the cortex, which is critical for higher-order cognition, were significantly more responsive to visual stimuli in participants with higher levels of lutein and zeaxanthin compared to those with low levels, suggesting improved visual memory and processing speeds.⁵⁰⁷ Furthermore, in a placebo-controlled trial of 91 participants (mean age 45 years) with low levels of macular pigment, a biomarker for levels of these carotenoids in the brain, daily supplementation with 10 mg lutein, 10 mg meso-zeaxanthin, and 2 mg zeaxanthin for 12 months significantly improved memory.⁵⁰⁸ Finally, in a placebo-controlled study of 62 older adults (mean age 73.7 years), supplementation with 12 mg lutein and zeaxanthin for 12 months was associated with a significant increase in both complex attention and cognitive flexibility.⁵⁰⁹

Pycnogenol

Pycnogenol is an extract from French maritime pine bark with potent anti-inflammatory and antioxidant properties that supports cognitive function and mental performance. Pycnogenol has been shown to combat oxidative stress, promote sustained attention, and improve memory.^537,538 Both preclinical and clinical research supports the use of Pycnogenol for cognitive support.^539-541 For instance, Pycnogenol has been shown to attenuate the progression of cognitive impairment in patients with Parkinson disease.⁵⁴² Furthermore, in a mouse model of Alzheimer disease, Pycnogenol supplementation decreased the number of β-amyloid plaques and improved some aspects of memory.⁵⁴³

A 12-month clinical trial that enrolled 44 healthy subjects aged 55‒70 with high oxidative stress found 100 mg Pycnogenol daily appeared to improve cognitive function.⁵⁴⁴ A separate 12-week trial involving 30 healthy individuals and 29 matched controls aged 35‒55 found supplementation with 150 mg Pycongenol daily promoted cognitive function and reduced oxidative stress.⁵⁴⁵ As of mid-2021, a randomized controlled trial was underway in Australia to investigate the efficacy of 150 mg Pycnogenol daily in improving cognitive performance and reducing cognitive decline in elderly participants aged 60‒75.⁵⁴⁶

Multivitamin/Multi-nutrient Formulas

The effect of multivitamins on cognitive trajectory has been examined in several relatively small studies over the years. When considered collectively, the results of these studies have suggested that multivitamins may provide small benefits for some aspects of cognitive function.⁵⁷⁵ However, most studies have been short-term, and the multivitamin formulations used have differed.

Two studies of multivitamins and cognitive function stand out for their methodological strengths and sizes. These trials occurred in the context of the Physician’s Health Study II and Cocoa Supplement and Multivitamin Outcomes Study for the Mind (COSMOS-Mind) trial. The first trial enrolled over 5,900 men aged 65 years or older. Participants took a multivitamin and underwent periodic cognitive assessments. The mean follow-up time was about 8.5 years. Multivitamins did not provide cognitive benefits in this study.⁵⁷⁶ On the other hand, in the COSMOS-Mind trial, over 2,200 participants aged 65 and older were randomized to take a multivitamin and/or cocoa flavanols or a placebo. They were followed-up with cognitive assessments annually for three years. Subjects taking the cocoa flavanols did not exhibit slowing of cognitive impairment. However, subjects taking the multivitamin showed improvements (relative to placebo) in global cognitive function, episodic memory, and executive function.⁵⁷⁷ Further long-term, randomized, controlled trials are needed to clarify the role of multivitamin/multi-nutrient supplementation on cognitive function.

Vitamin K2

“Vitamin K2” refers to a group of at least 15 related compounds known as menaquinones (MKs).⁶¹⁰ Among the menaquinones, MK-4 and MK-7 have been associated with age-related changes in cognitive function.^611,612 For example, in a study examining 365 elderly participants, a higher brain concentration of MK-4 was associated with a 17-20% lower risk of MCI.⁶¹³

Several in vitro and animal model studies have investigated the mechanisms by which menaquinones may support brain health and cognitive function. These investigations have shown that menaquinones are involved in the synthesis of sphingolipids, which are lipids in neural cell membranes that help facilitate cellular signaling, synaptic plasticity, and myelin formation.⁶¹⁴ Menaquinones may also help preserve the expression of tyrosine hydroxylase, an enzyme involved in the production of dopamine, norepinephrine, and epinephrine.^611,612 MK-4 and MK-7 specifically have been shown to inhibit the upregulation of proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and to protect against oxidative stress.^615-618

In a preclinical study examining the effect of MK-7 on cognitive aging, 3-month-old rats were given high-dose vitamin K2 (MK-7) over 17 months. Their cognitive function was compared with that of control rats given a placebo. Vitamin K2 administration improved memory performance, reduced social anxiety and depressive-like behavior, and decreased inflammation, suggesting an attenuation of age-related changes in the brain.⁶¹⁹

Although low levels of vitamin K2 have been associated with progression of neurodegenerative diseases, such as Parkinson disease, clinical studies are required to examine the association between vitamin K2 and cognitive decline.^611,620

Vitamin D

Although vitamin D is often thought of in the context of bone and immune health, it also exerts substantial activity within the central nervous system.The vitamin D receptor, which influences cellular function and gene expression, can be found on nearly every cell in the body, including the cells of the central nervous system (eg, neurons, astrocytes, and microglial cells). And some of these cells can synthesize the biologically active form of vitamin D (1,25-dihydroxyvitamin D), which suggests the active form is important in the central nervous system.^621,626

An observational study published in 2022 evaluated data on vitamin D levels and brain aging in 1,865 subjects with an average age of 52 years. Structural MRI data was obtained on whole brain volumes, gray matter volumes, and hippocampal volumes. Among the men in this study, vitamin D deficiency, defined as 25-hydroxyvitamin D levels under 16.08 ng/mL, was significantly associated with neuroimaging patterns of advanced brain aging. In addition, vitamin D levels were positively associated with total brain and gray matter volumes.⁶²²

A prospective cohort study published in 2023 assessed vitamin D exposure and dementia occurrence across 12,388 dementia-free persons. Vitamin D exposure compared with no exposure was associated with significantly longer dementia-free survival and a 40% lower dementia incidence rate. Dementia incidence rates across groups remained significantly lower when adjusted for age, sex, education, race, cognitive diagnosis, depression, and apolipoprotein E4 (APOE4) status.⁶²³

In a randomized-controlled trial, 183 participants aged 65 years and older with mild cognitive impairment received 20 mcg (800 IU) vitamin D daily or placebo for 12 months. At 12 months, those in the vitamin D group had significantly greater improvements in overall cognitive function, as measured with a variety of tests assessing memory, attention, and processing; increased telomere length; and reduced oxidative stress compared with the placebo group.⁶²⁴

In a larger randomized controlled trial, 3,424 participants aged 60 years and over received either 50 mcg (2,000 IU) vitamin D or placebo daily for 2–3 years. Changes in scores on several cognitive assessments and a composite of these cognitive assessments were evaluated at baseline and at the end of follow-up. The results showed that vitamin D supplementation only provided better cognitive maintenance over placebo in the Black participants. Among possible explanations for this finding is that Black participants had lower 25-hydroxyvitamin D status at baseline.⁶²⁵

An approach that includes healthy diet, physical activity, adequate sleep, and mentally and socially stimulating activities is more important for preserving cognitive health with age than any individual intervention.^1,4,143

Physical Activity

Staying physically active throughout life is critical to maintaining healthy cognitive function. Exercise has been linked to slower rates of age-related brain atrophy in key areas of the brain involved in cognitive decline, and being physically active in midlife is associated with slower cognitive decline and reduced risk of cognitive impairment and dementia later in life.¹⁴⁴

Preclinical research suggests exercise can stimulate production of growth factors, such as BDNF, which promote neuroplasticity. Exercise also improves cerebrovascular function, supports formation of new blood vessels in the brain, and increases blood flow.¹⁴⁴

A large body of evidence indicates that any type and amount of physical activity is better than none when it comes to cognitive health. It is clear that both aerobic exercise and strength training can prevent or delay cognitive decline in older adults, regardless of their current cognitive status.¹⁴⁵ Even seated exercises have cognitive benefits for older patients who are unable to exercise upright.¹⁴⁶ Exercise therapy has been found to improve the functional connectivity of various brain networks, which is thought to underlie the improvements in cognitive function. In a clinical trial of 33 older adults, roughly half of whom had mild cognitive impairment and the other half had intact cognition, cognitive function was assessed before and after a 12-week exercise therapy intervention. The intervention included walking 30 minutes a day, four days per week for the first four weeks. During the remaining weeks, participants performed 10 minutes of warm-up and cool-down in addition to 30 minutes of walking (50 minutes per session) four days per week. Exercise therapy resulted in an improvement in cardiorespiratory fitness, measures of cognitive function, and functional connectivity between brain networks.⁶³⁸

Diet

Healthy eating patterns help preserve cognitive function and reduce the risk of neurodegenerative disease and age-related cognitive decline.^520-522 Diet may also influence the body’s inflammatory environment, which becomes proinflammatory with age and can contribute to cognitive decline. In fact, an observational study of over 1,000 individuals found that higher intake of fruits, vegetables, beans, and tea or coffee was correlated with a stronger anti-inflammatory diet, and those who consumed less of these foods (ie, a less anti-inflammatory diet) were at a 21% higher risk of developing dementia.⁵⁷⁸

Three diets in particular have demonstrated an ability to protect against cognitive decline:

• a diet based on traditional Mediterranean dietary patterns
• DASH, or Dietary Approaches to Stop Hypertension
• the MIND diet, or Mediterranean-DASH Intervention for Neurodegenerative Delay

Mediterranean diet. Numerous studies have shown that a Mediterranean dietary pattern is associated with less cognitive decline and reduced risk of dementia.^199,522 With its emphasis on extra virgin cold-pressed olive oil; vegetables including leafy greens; fruits; grains; nuts and legumes; moderate amounts of seafood, milk products, eggs, and red wine; and low intake of sweets and meat,⁵²³ the traditional Mediterranean diet provides ample amounts of critical nutrients such as mono- and polyunsaturated fatty acids, antioxidants, vitamins, minerals, and phytonutrients. It can be used as a template that can be adapted to include local and seasonal availability of specific foods.^143,198

The Mediterranean diet has been the subject of PREDIMED, a large, randomized, controlled, multi-center, ongoing trial in Spain. Multiple studies within the PREDIMED cohort found that the Mediterranean diet improved cognitive and memory performance,⁵²² while another found those following a Mediterranean dietary pattern tended to have higher plasma BDNF levels.⁵²⁴ A study including 832 subjects examined participants every two to three years for up to 18 years and found that those whose diets most closely resembled a Mediterranean dietary pattern experienced significantly less cognitive decline than those whose diets least resembled a Mediterranean diet.²⁰¹

A study based on data collected over 16 years from nearly 28,000 men participating in the Health Professionals’ Follow-up Study found that those whose diets were most Mediterranean-like were 36% less likely to report poor subjective cognitive function than those whose diets were least Mediterranean-like.²⁰² Examining the brains of cognitively normal older-age subjects has revealed that adherence to a Mediterranean-like dietary pattern is associated with reduced β-amyloid accumulation. The components of the diet most closely linked with this effect were high fruit and vegetable consumption and moderate wine consumption.^203,204

• Extra virgin olive oil. While it appears that the combination of eating habits comprising the Mediterranean diet is the key to its efficacy, the high consumption of extra virgin olive oil (EVOO) featured in the diet is thought to be an important reason for its protective effect on cognition. Several preclinical studies indicate polyphenols in EVOO can reduce β-amyloid and tau accumulation and toxicity, and may modulate microRNA profiles.^205-207 One clinical trial in 285 older adults compared three diets: Mediterranean diet supplemented with as much as 1 liter per week (more than ¼ cup per day) of EVOO; Mediterranean diet including 30 grams per day of mixed nuts; and a low-fat diet. After 6.5 years, the olive-oil-supplemented group had better cognitive performance than the other two groups.²⁰⁸

DASH diet. The DASH diet, developed based on research sponsored by the National Institutes of Health (NIH), shares many important characteristics with the Mediterranean diet. It focuses on vegetables, fruits, and whole grains, while including fat-free or low-fat dairy products, fish, poultry, beans, nuts, and vegetable oils. Foods high in salt (sodium), including processed foods, restaurant foods, olives, and some cheeses and seafoods, are restricted. Sugars from sweets, sweetened foods, and sugar-sweetened beverages are to be limited, as are foods high in saturated fat. These include red meat and fatty meats, full-fat dairy products, and tropical oils such as coconut, palm kernel, and palm oils. A DASH diet is high in magnesium, potassium, and calcium, as well as protein and fiber.^525,526

The DASH diet has been demonstrated to reduce high blood pressure, improve lipid levels, and increase circulating levels of antioxidants including glutathione.^525-529 An observational study in over 16,000 women over the age of 70 years found that long-term adherence to DASH diet principles was associated with better average cognitive function and verbal memory. This difference was comparable to being one year younger in age.⁵³⁰

In a randomized controlled trial, 160 sedentary men and women over age 55 who had cognitive impairment but no dementia, and cardiovascular risk factors, undertook either aerobic exercise, a DASH diet, both, or a health education program. There was some improvement in executive function in the DASH diet group. The largest and most significant improvements compared to health education alone were in subjects who combined aerobic exercise and DASH diet.⁵³¹

MIND diet. The MIND diet was developed as a hybrid of Mediterranean and DASH diets specifically targeted to improve brain health and retard loss of brain function. Like the Mediterranean and DASH diets, the MIND diet emphasizes plant foods and limits intake of animal foods and foods high in saturated fat. However, the MIND diet encourages high consumption of berries and green leafy vegetables, but de-emphasizes fruit overall, dairy, potatoes, and fish—all departures from DASH and Mediterranean dietary patterns.⁵³²

In an observational study, the MIND diet adherence score compared favorably to DASH or Mediterranean diet scores for predicting cognitive decline. Subjects who most closely adhered to the MIND diet had a rate of cognitive decline similar to that of people 7.5 years younger. A prospective study cohort found that the highest adherence scores for all three diets were associated with a substantially lower risk of developing Alzheimer disease, compared to the lowest adherence score.⁵³² In an Australian cohort of 1,200 individuals followed-up for 12 years, a MIND dietary pattern lowered the risk of cognitive decline by 53%.⁵³³

Continued study of the MIND diet found it is associated with significant protection against neurodegenerative disease and cognitive decline. These effects have been comparable, or even superior, to the DASH and Mediterranean diets for these purposes.⁵³⁴ Furthermore, a high level of adherence to the MIND diet has been shown to slow the rate of cognitive decline after stroke.⁵³³ Finally, a 2021 study of recently deceased individuals found that greater adherence to the MIND diet was associated with better cognition regardless of underlying brain pathologies such as Alzheimer disease. In this study, researchers analyzed dietary, medical, and autopsy records of 569 people who had recently died. The link between better cognition and MIND diet scores held even when the investigators restricted their analysis to people with autopsy evidence of Alzheimer disease or those without a history of cognitive impairment. These findings suggest greater MIND diet adherence supports healthy cognition regardless of underlying neurocognitive pathology.⁵⁷⁹

On the other hand, some evidence suggests that a calorie-restricted MIND diet is no more effective at improving cognition than a standard calorie-restricted diet. In a controlled trial, 604 cognitively unimpaired people (65–84 years of age) with overweight or obesity and a history of familial Alzheimer disease were randomized to a control diet (mild calorie restriction only) or MIND diet plus mild calorie restriction for three years. The control diet group focused on portion control whereas the MIND diet group increased consumption of foods found in the MIND diet. Both groups displayed a similar increase in cognitive function, measured by a composite score obtained from a battery of 12 tests, and no significant difference in physical brain characteristics measured with MRI.⁶²⁷ 

Sleep

Sleep is a critical time for brain rest and repair, and both acute and chronic sleep disturbances have measurable negative impacts on physical, emotional, and cognitive health. Long-term sleep deprivation and chronic sleep restriction or fragmentation damages neuronal function and contributes to stress, mood symptoms, and cognitive dysfunction.¹⁷⁸ In healthy older adults, subjective cognitive symptoms are reported more often in those also reporting sleep disturbances.¹⁷⁹

Aging is naturally associated with diminished sleep quantity and quality,^180,181 which may influence cognitive function by disrupting circadian regulation and stress hormone signaling, and promoting systemic inflammation, metabolic disturbance, and fat deposition.^182,183 Furthermore, poor sleep may influence cognition through epigenetic changes affecting neuroplasticity.¹⁸³

According to large meta-analyses of research into this relationship, the optimum amount of sleep for healthy cognitive function appears to be 7–9 hours per night, with both shorter and longer sleep durations associated with increasing risks of cognitive decline, mild cognitive impairment, and dementia.^{184,185580,581}

Sufficient daily activity and a nighttime environment that promotes sleep may help older people struggling with sleep disorders. Strategies that have demonstrated some effectiveness include^181,186,187:

• Daytime activities. Because too little or too much activity during the day can contribute to sleep problems at night, maintaining a balanced schedule of daily activities and engagements may help prevent daytime napping and facilitate better nighttime sleep.
• Meditation. Mind-body therapies and meditations promote relaxation and may increase time asleep.
• Cognitive behavioral therapy. Cognitive behavioral interventions for insomnia focus on reframing negative thought patterns around sleep.
• Sleep-enhancing devices. Use of devices that improve the sleep environment (eg, earplugs, eye masks, white noise machines, weighted blankets, and devices that play sleep-inducing music) have all demonstrated some effectiveness in reducing sleep disturbance.
• Daytime bright-light therapy. Bright light therapy may help increase daytime activity, reduce daytime napping, and reset the circadian clock, thereby assisting in restoring normal sleep patterns.

A variety of other important considerations for healthy sleep are reviewed in Life Extension’s Insomnia protocol.

Essential Oils/Odorants

The olfactory system is responsible for the sense of smell and is highly integrated with various regions of the brain such as the hippocampus, a structure that plays a significant role in learning and memory. As a result, aromatherapy and essential oils are emerging as safe, non-nutritional interventions to support brain and cognitive health. Animal studies suggest that aromatherapy helps improve cognitive dysfunction by preserving synaptic density, supporting neurotransmission, and reducing the levels of beta [ß]-amyloid and abnormally phosphorylated tau.^628-630 Several clinical studies have shown that olfactory training, sometimes called olfactory enrichment, can improve mood, enhance memory and cognition, and positively modify brain structure in healthy individuals as well as those experiencing cognitive decline.⁶³¹

A study including 36 healthy young individuals found that six weeks of olfactory training for 20 minutes per day resulted in increased volume of various brain regions as measured with MRI.⁶³² A separate study including 43 adults aged 60–85 not diagnosed with cognitive decline or dementia exposed participants to seven different odorants (rose, orange, eucalyptus, lemon, peppermint, rosemary, and lavender) per week nightly for two hours; trace amount of odorant was used as control. Those in the odorant group exhibited a significant improvement on a test of learning and memory, as well as improved functioning of a brain circuit involved in learning and memory.⁶³³ Olfactory training twice daily for five months with odors of lime, cloves, eucalyptus, and rose was found to increase scores on a test of cognitive function, improve subjective well-being, decrease depressive symptoms, and reduce cognitive age in healthy adults aged 50–84 years.⁶³⁴

In a randomized controlled trial, 37 patients with mild cognitive impairment were randomized to olfactory training or placebo twice daily for four months. Olfactory training was associated with improved global cognition that correlated with increased thickness of the hippocampus and other regions involved in cognitive function.⁶³⁵ Aromatherapy with rosemary and lemon oils in the morning and lavender and orange in the evening was also found to improve cognitive function in patients with Alzheimer disease after 28 days.⁶³⁶ A systematic review of seven studies also found that olfactory training can act as a simple and convenient intervention to help improve and maintain cognitive function.⁶³⁷

Mental Activity

Engaging in mentally stimulating activities has been shown in numerous studies to be important for cognitive health during all life stages. It is thought that education and other forms of mental stimulation build cognitive reserve (ie, the brain’s ability to use alternative neuronal pathways to accomplish cognitive tasks) over a lifetime. Having greater cognitive reserve may delay the onset of symptoms related to aging or pathological changes in the brain.^6,147

Higher education level and bilingualism over a lifetime have protective effects on cognitive function, and early research suggests educational pursuits and language acquisition at older ages may still benefit some aspects of cognition.^6,148,149 A meta-analysis of studies found that musical practice is associated with preservation of a variety of aspects of cognitive function, including those affected by aging. The effect is strongest in those with long-term musical training, but is also observed after short-term musical training later in life.¹⁵⁰

Mentally stimulating leisure activities have been linked to cognitive benefits in multiple studies. For example, in one study in 100 cognitively healthy older adults, long-term jigsaw puzzlers were found to have higher function in all aspects of cognitive ability examined.¹⁵¹ There is some evidence that doing Sudoku and crossword puzzles can benefit the aging brain.^152,153 A study in 16,572 participants aged 65–100 years found that higher frequency of engagement in word or number games was associated with better cognitive performance on tests of memory, numeracy, and verbal fluency both at baseline and after two years. Even those who began playing word or number games after the beginning of the study demonstrated better cognitive function at the end than those who did not play word or number games regularly. The effect was equally strong in participants of all ages and more pronounced in those with a lower level of education.¹⁵⁴ Another study found that activities such as computer use, crossword puzzles, handicrafts, and educational courses were each associated with reduced cognitive decline over one year.¹⁵⁵ Early research suggests mentally stimulating computerized programs may be useful for improving cognitive performance in patients with mild cognitive impairment and dementia.¹⁵⁶

Stress Reduction

Chronic stress, anxiety, depression, and sleep disturbance are often inter-related. These conditions have well-established detrimental effects on brain structure and function, and are associated with increased risk of dementia.¹⁵⁷ Stress reduction techniques, such as meditation and yoga, may have a role in slowing age-related cognitive decline and preventing cognitive impairment.^157,158 Mindfulness meditation, for example, has consistently been found to positively affect brain structure, function, and plasticity, including in regions of the brain associated with cognitive dysfunction.⁶ Long-term yoga practitioners have been found to be less likely to have age-related brain atrophy and perform better on some cognitive tests compared with those not practicing yoga.^159,160 Other research found similar effects in long-term meditators.¹⁶¹ Looking at cognitive function in subjects with a wide age range, one study determined that long-term yoga practitioners and meditators had slower cognitive decline and more resilient neuronal networks than those with neither practice.¹⁶²

Preliminary studies have indicated that meditation practice can improve memory, attention, and executive function in older adults,^158,163 and may mitigate age-related cognitive decline.¹⁶⁴ Mindful movement therapies such as tai chi, yoga, and walking meditation also have positive effects on quality of life, mood, and cognitive function.¹⁶⁵ In one randomized controlled clinical trial in 118 participants with an average age of 62, an eight-week Hatha yoga program involving postures, breathing, and meditation exercises improved performance on tests of attention and information processing speed.¹⁶⁶

Social Engagement

Social engagement, like physical and mental activity, may be an important mediator of healthy brain function throughout life.¹⁶⁷ A growing number of studies indicate high social engagement and strong social networks are correlated with reduced age-related cognitive decline, mild cognitive impairment, and dementia.^167,168 On the other hand, progressive loss of cognitive function, as well as physical function, can lead to diminished strength of social networks and increased isolation, contributing to further cognitive losses.^169-171

Strong social networks have been correlated with better cognitive function in older adults and reduced likelihood of experiencing anxiety and depression symptoms in those with mild cognitive impairment.¹⁷² One study found that cognitive decline in older men and women over an eight-year period was mitigated by regular engagement in social activities, regardless of cognitive status at the beginning of the study.¹⁷³ Similarly, social engagement was correlated with slower cognitive decline in 543 cognitively healthy participants, initially 67-years of age, who were monitored for eight years.¹⁷⁴ Volunteering was identified in one study as a particular predictor of cognitive resiliency with aging, which may be due in part to the combined social and cognitive aspects of many volunteer activities.¹⁷⁵

Participating in group social activities may become more important to cognitive health at older ages.¹⁷⁶ Even in the very old, social engagement appears to be beneficial; participation in arts, crafts, and social activities were all noted as protective against mild cognitive impairment in a group of 256 people aged 85 years and older who were cognitively normal at the beginning of the study and were monitored for approximately four years.¹⁷⁷

Coffee

Numerous preclinical and clinical studies have examined the potential for drinking coffee to help prevent cognitive decline. Caffeine and coffee are recognized to improve short-term memory and cognition, and some research indicates long-term coffee consumption could protect against dementia and cognitive decline. Furthermore, preclinical models have demonstrated plausible biological mechanisms for bioactive components in coffee to be neuroprotective.²⁰⁹ For instance, in a three-year study in 145 cognitively healthy elderly participants, moderate-to-heavy coffee drinking was linked to reduced cognitive decline, as well as better preservation of brain white matter and cerebral blood flow.²¹⁰ Similarly, an analysis of 11 prospective studies found the highest levels of coffee consumption were associated with a 27% lower risk of Alzheimer disease.²¹¹ However, some studies have found that smaller amounts also appear to protect cognitive function. An analysis of nine prospective studies concluded that optimal protection resulted from 1‒2 cups of coffee per day,²¹² while other studies suggest coffee’s effects on cognition and the brain are complex and require further study.^213-215

Caloric Restriction

Caloric restriction, a dietary intervention in which calorie intake is reduced but adequate nutrient intake is preserved, has been shown to delay the onset of age-related diseases and extend lifespan in many organisms.²¹⁶ This effect is thought to be due to a triggering of resilience mechanisms that enhance cellular resistance to stress.^217,218 This effect is known as hormesis.

In rodent models, caloric restriction was associated with decreased neural stem cell senescence, increased neuroplasticity, and better cognitive performance.²¹⁸ Specifically, caloric restriction has been found in animal models to stimulate neural stem cell activity,²¹⁹ promote normal metabolism of phospholipids needed for myelin production,²²⁰ lower stress reactivity and stress-related changes in brain structure,²²¹ and induce epigenetic changes that support youthful gene expression in aging brains.²²² Some of the same metabolic and molecular changes and health benefits associated with caloric restriction in animals have been demonstrated in humans engaging in 25% caloric restriction or through an intermittent fasting strategy, combined with physical activity.²¹⁶

More information is available in Life Extension’s Caloric Restriction protocol.

Older age is the number one risk factor for age-related cognitive decline, as well as mild cognitive impairment and dementia. Women have a higher risk of dementia than men. Furthermore, a number of risk factors for late-life dementia have been identified, many of which have their strongest impact on late-life cognitive function when they occur in midlife.^21-23 These risk factors include:

• Sedentary lifestyle^21,22
• Low educational attainment^21,22
• Smoking^21,22
• Obesity^21,22
• Insulin resistance and type 2 diabetes^21,22,582
• Chronic inflammation⁵⁸²
• Hypertension^21,22
• High cholesterol levels^21,22
• Chronic kidney disease²¹
• Atrial fibrillation (a type of arrhythmia)²¹
• Cardiovascular disease²⁴
• Cerebrovascular disease⁵¹²
• Traumatic brain injury
• Depression²¹
• Sleep disorders²⁵
• Sleep apnea²⁶
• Hearing loss⁵⁸³
• High homocysteine levels²⁷
• Heavy metal toxicity²⁸

Figure 3: Cardiovascular disease, oxidative stress, inflammation, obesity, type 2 diabetes, and sleep disorders are all examples of factors that can contribute to cognitive decline and MCI.

Anticholinergic medications block the effects of acetylcholine and are used to treat a wide variety of illnesses, including asthma, chronic obstructive pulmonary disease (COPD), Parkinson disease, depression, and allergies, among other conditions.⁵¹⁰ In a recent study of 688 cognitively healthy older adults, the effect of anticholinergic medication on cognitive function was assessed over a 10-year period. Individuals who used anticholinergic medications at least once per week for more than six months at baseline had a significant, 1.5-fold increased risk of progression to mild cognitive impairment. The increase in risk associated with anticholinergic medication use was particularly pronounced among individuals with the APOE ε4 genotype, who had a 2.7-fold risk increase compared with those not using anticholinergic medications who did not have the APOE ε4 genotype. Furthermore, anticholinergic medication use in individuals with biomarkers of Alzheimer disease in their cerebrospinal fluid was associated with a nearly 5-fold increase in risk for development of mild cognitive impairment. Anticholinergic use was also associated with a more rapid decline in memory and language, particularly among those with the APOE ε4 genotype or with cerebrospinal fluid markers for Alzheimer disease.⁵¹¹

Cognitive decline is a complex process with multiple overlapping mechanisms that are not fully understood. Below is a discussion of current understandings regarding some of the processes that contribute to cognitive decline in older age.

Stem Cell Senescence

Groundbreaking studies in the 1990s revealed specialized regions of the human brain harbor stem cells, known as neural stem cells, that may continue to repair and regenerate brain tissue throughout life.^8,32 Growth factors such as BDNF and other signaling factors in the brain environment appear to stimulate neural stem cell proliferation and the formation of neurons and neuronal connections.^33,34 The ability of the brain to form new neurons and connections and rearrange neural networks in response to signals from the environment is known as brain plasticity, or neuroplasticity.³²

With age, neural stem cells become less responsive to stimulation and stem cell signaling can become dysregulated.³⁵ This condition, known as stem cell senescence, is thought to be a major contributing factor in the diminishing plasticity that characterizes the aging brain.^36-38

Circadian Rhythm Disturbance

The circadian rhythm is a natural cycle that affects the brain and the rest of the body in many important ways. Circadian clocks synchronize metabolic, physiologic, and behavioral rhythms with environmental cycles, such as light-dark cycles and daily eating patterns.^39,40 Among the many bodily functions regulated by circadian signaling are acquisition of learning and consolidation and recall of memories.^40,41 Desynchronization of the circadian clock, such as through shift work, chronic stress, and sleep disorders, can contribute to cognitive decline.⁴⁰ Circadian rhythm disruption is thought to interfere with neurogenesis and reduce neuroplasticity.⁴² Melatonin is one hormone that plays a role in the circadian rhythm and its decline with increasing age may be a contributing factor.⁵⁸⁴

Cerebrovascular Dysfunction

The term “cerebrovascular” refers to the blood vessels supplying the brain. Cerebrovascular dysfunction refers to various (often age-related) pathologies of the brain’s circulatory system, including atherosclerosis, hypertension, and amyloid deposition in blood vessels.^512,585 Another age-related cerebral blood vessel defect is arterial stiffness, in which vessels become less responsive to changes in blood pressure, and to oxygen and nutrient demands.⁵¹³ These and other changes can eventually result in an interruption of cerebral blood flow, depriving the brain of oxygen and fuel.^512,514,515 Stroke, the most serious manifestation of cerebrovascular problems, occurs when blood clots or hemorrhages (uncontrolled bleeding) arise in cerebral blood vessels. Cognitive function is often impaired after a stroke.^516-518 Another possible outcome of cerebrovascular dysfunction is transient ischemic attack (sometimes called a mini-stroke), which is a temporary decrease in blood supply that can negatively affect cognition.⁵¹⁹

The blood vessels that supply the brain have a unique structural feature called the blood‒brain barrier, made up of specialized junctions between endothelial cells (ie, the cells that form the inner lining of blood vessels). In healthy individuals, these junctions exert tight control over the movement of compounds between the blood and the brain. The blood‒brain barrier has been observed to lose integrity with age, becoming increasingly permeable to potential toxins and pro-inflammatory factors.¹⁴

Orthostatic hypotension—low blood pressure upon standing after sitting or lying down—has been associated with cognitive decline. In a population-based cohort study including 2,532 dementia-free participants aged 60 or older, orthostatic hypotension was associated with an increased risk of dementia and cognitive decline. Participants with orthostatic hypotension (defined as a decrease of ≥20/10 mmHg in systolic/diastolic blood pressure upon standing) with no cognitive impairment at baseline had a 40% increased risk of developing dementia during 12 years of follow-up, and those exhibiting cognitive impairment had a 54% increased risk of progression to dementia.⁵⁸⁶ These results suggest orthostatic hypotension, even when asymptomatic, is associated with increased risk of dementia and accelerated progression from cognitive impairment to dementia in older adults.

Blood pressure variability (BPV) is also being investigated as a risk factor for cognitive impairment and dementia. While it is known that BPV in midlife can increase the risk of late-life dementia, the effect of BPV on cognition in older adults without cognitive impairment remains unclear. An assessment of data from the ASPREE clinical trial, which includes nearly 20,000 participants who were free of dementia and significant cognitive impairment at time of enrollment, suggests a link between higher BPV and cognitive deficits in older adults (aged 70 years or older or 65 and older if a United States minority) without previous major cognitive impairment. Individuals displaying the highest degree of BPV had an increased risk of dementia and cognitive decline compared with those in the lowest tertile of BPV. Interestingly, there was a sex-association with increased risk of dementia in men, but not women.⁵⁸⁷

Neuroinflammation

Aging is associated with elevated inflammatory signaling involving activated microglia, astrocytes, blood vessel endothelial cells, and other cell types, causing neuroinflammation. This leads to increased production of free radicals and other neurotoxins that damage neurons and trigger neuronal degeneration.^11,47 Neuroinflammation also degrades the blood‒brain barrier, exposing neurons to more potential toxins.⁹ Conditions associated with systemic inflammation, such as lack of physical activity, poor diet, obesity, and type 2 diabetes, have all been associated with age-related cognitive decline and dementia.^21,48 An unhealthy gut microbiome is another possible source of inflammatory signaling that may contribute to deterioration of the blood‒brain barrier and neuroinflammation.⁴⁹

Mitochondrial Dysfunction & Oxidative Stress

The brain uses about 20% of the resting body’s oxygen, and roughly 85% of that oxygen is consumed by brain cell mitochondria. The brain is particularly sensitive to mitochondrial dysfunction, and free radical production in the brain is exceptionally high. Free radical production in a healthy brain is balanced by powerful antioxidant defenses; however, in an aging brain, antioxidant enzymes like glutathione reductase and superoxide dismutase (SOD) are less active, leading to an imbalance that favors free radical production and creates an environment of high oxidative stress.^47,50

Oxidative stress damages cellular and mitochondrial DNA, membranes, and proteins, contributing to decreased brain cell activity and increased mitochondrial dysfunction. Mitochondrial dysfunction results in lower ATP production and even more free radical generation,⁵⁰ and contributes to depletion of neural stem cells.⁵¹ Reduced energy for metabolic activity within brain cells leads to their diminished ability to engage in normal neuronal activities, including maintenance of cell membranes and production of myelin,¹³ as well as activities related to learning, memory, and cognition.⁴⁷ In addition, oxidative stress increases inflammatory signaling, exacerbating neuronal damage and loss.⁴⁸

Metabolic Disturbance

Metabolic disturbances like insulin resistance and obesity are implicated as contributors to cognitive impairment and dementia. It is thought that systemic inflammation caused by insulin resistance and obesity may drive neuroinflammation, brain insulin resistance, brain mitochondrial dysfunction, and brain oxidative stress. These conditions eventually lead to neuronal damage and cognitive decline.^52,53

Disordered blood lipid levels and high blood glucose levels have consistently been found to correlate with cognitive dysfunction,^52-54 and type 2 diabetes has been correlated with increased risk of mild cognitive impairment, as well as its progression to dementia.⁵⁵ In addition, Alzheimer disease increases the risk of developing type 2 diabetes, suggesting a bidirectional relationship.⁵⁶ Although the mechanism underlying the connection is not fully understood, the relationship between insulin resistance and Alzheimer dementia in particular is so compelling that it is sometimes referred to as “type 3 diabetes.”⁵⁷

Abnormal Protein Accumulation

Beta [β]-amyloid and tau proteins occur normally in the brain, but when high levels of these proteins accumulate, they can trigger structural changes that disrupt neuronal function and signal transmission.^2,64 In the aging brain, β-amyloid proteins accumulate in the spaces between neurons due to increased production, reduced clearance, or both.^1,14 At high concentrations, β-amyloid proteins coalesce and form plaques around neurons.⁶⁴ Tau proteins become damaged through a chemical process called phosphorylation. Aggregates of phosphorylated tau inside neurons trigger neurofibrillary tangle formation.⁶⁴ Such plaques and tangles interfere with normal neuron-to-neuron communication, and are the hallmarks of Alzheimer disease, but recent studies revealed β-amyloid and phosphorylated tau may begin to accumulate decades before the onset of clinical dementia.^65-68

High levels of β-amyloid and tau in the brain, as well as higher tau levels in the blood, have each been independently correlated with cognitive decline in the elderly and disease progression in those with mild cognitive impairment.^65,69,70 While the nature of the relationship between abnormal protein accumulation and cognitive decline is not fully understood, phosphorylated tau proteins in particular appear to interfere with synapse function and induce a neuroinflammatory process leading to neuronal dysfunction even before tangles develop.^65,71

Epigenetics

“Epigenetics” is a term used to describe biological phenomena that affect how cells use the information stored in the genetic code. Epigenetic processes emphasize or de-emphasize the information contained in sections of the genome. Sections emphasized by epigenetic processes are said to be “expressed,” and de-emphasized sections are “silenced.” Epigenetic processes do not change the genetic code, but rather how cells “read” the code. Factors such as lifestyle habits, nutrition, and the environment (eg, exposure to air pollution) can influence epigenetic gene expression and silencing.

There is increasing evidence that epigenetics play a crucial role in learning, memory, and cognition in older adults and influence development of cognitive impairment and dementia.⁷² For example, epigenetic alterations affecting the brain’s circadian clock have been noted to impact function in key brain regions associated with cognitive decline.⁷³ Factors that may trigger epigenetic changes associated with cognitive decline and dementia include disordered breathing patterns (eg, hyperventilation syndrome), poor diet, alcohol overconsumption, and sleep deprivation.⁷⁴

Disrupted Homocysteine Metabolism

Homocysteine is an amino acid derivative that has detrimental effects on blood vessels, contributing to vascular inflammation, thickening of the vessel walls, and endothelial dysfunction. It is a contributing factor in atherosclerosis and increases the risk of stroke. Homocysteine’s effects on brain function may be related to its impact on cerebral blood vessels,⁷⁵ but some evidence also suggests homocysteine increases oxidative stress and neuroinflammation, and may have direct neurotoxic effects.⁷⁶

A consensus statement by a panel of experts published in the Journal of Alzheimer’s Disease in 2018 stated that moderately elevated blood homocysteine levels (>11 mmol/L) are a contributing cause of age-related cognitive decline.²⁷ High homocysteine levels have been linked to brain atrophy,⁷⁷ and have consistently been associated with an increased risk of cognitive impairment, dementia, and Alzheimer disease.²⁷ Homocysteine is converted into cysteine via a pathway requiring pyridoxine (B6), or into methionine through a chemical process called methylation that is dependent on the B vitamins folate (B9) and cobalamin (B12). Folate and B12 deficiencies are common in the elderly and are the main cause of hyperhomocysteinemia.⁷⁶ Treatment with these B vitamins has been shown to reduce homocysteine levels, slow brain atrophy, inhibit cognitive decline, and improve memory.^27,77

Fibrinogen & Cognitive Decline

In a paper published in 2019, scientists at the Gladstone Institutes in San Francisco demonstrated that the blood-clotting protein fibrinogen, which can enter the brain after vascular damage weakens the blood‒brain barrier, may contribute to cognitive decline.⁷⁸ Once fibrinogen enters the brain, the researchers found, it forms deposits that activate certain types of microglial cells (the immune cells of the central nervous system). Microglial activation generates reactive oxygen species and damages the dendritic spines, destroying the synaptic connections between neurons and causing cognitive decline. The scientists demonstrated that even very small quantities of fibrinogen in healthy brains caused a loss of synapses as seen in Alzheimer disease—and even in the absence of amyloid plaques. Blocking fibrinogen from binding microglia reduced synaptic deficits and cognitive decline in a mouse model of Alzheimer disease. The vascular component of Alzheimer pathology could be a reason why clinical trials aimed solely at reducing amyloid plaque have been unsuccessful. Combination therapies that address vascular changes as well as amyloid deposits may prove to be more successful in the future.

Several earlier studies established the connection between fibrinogen levels and cognitive decline. In a study of over 2,300 middle-aged to elderly subjects, higher plasma fibrinogen levels at baseline were predictive of cognitive decline after five years.⁷⁹ Another study by the same research group linked a specific genotype associated with cognitive decline to higher fibrinogen levels.⁸⁰ Higher fibrinogen levels after ischemic stroke have also been associated with poorer cognitive outcomes.⁸¹

Hormone Imbalance

The brain is an integral part of the body’s hormonal network, regulating hormone production and responding to hormone signals. The hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis demonstrate the integrated relationship between the brain and hormone-producing glands. Hormones such as cortisol, pregnenolone, dehydroepiandrosterone (DHEA), estrogen, and testosterone affect brain structure and function. Age-related diminishment in levels of these hormones and dampening of the brain’s responsiveness to hormone signaling may impact susceptibility to cognitive decline and dementia.⁸²

Estrogen. Estrogen modulates brain function by enhancing cerebral blood flow, activating nerve growth factors, and preventing neuronal damage. It also appears to have a critical impact on mitochondrial energy production. In women, the drop in estrogen levels that occurs during perimenopause may be a contributing factor in age-related cognitive decline.^83,84 Indeed, many women report changes in cognitive function around the time of menopause, although objective measures suggest this may be more profound with surgical menopause than natural menopause. Clinical trials in women suggest initiating estrogen therapy soon after menopause may have the greatest benefit in lowering dementia risk later in life. In fact, initiating estrogen therapy at an older age has been associated with no effects or detrimental effects on cognitive function.^84,85 One complicating factor in clinical trials is the use of progesterone in combination with estrogen: while natural progesterone may augment the neuroprotective effects of estrogen, synthetic progestins such as medroxyprogesterone acetate (MPA) (which are typically used with estrogen in postmenopausal hormone therapy) appear to have the opposite effect.⁸⁴ More information is available in Life Extension’s Female Hormone Restoration protocol.

Testosterone. Testosterone is an important regulator of cognition and mood, and lower levels in middle-aged and elderly men have been associated with depressive symptoms, worse cognitive performance, and increased risk of dementia in some studies.⁸⁶ In men 70 years and older, greater reductions in testosterone levels have been correlated with increased cognitive decline.⁸⁷ Some research suggests testosterone therapy may improve mental health, quality of life, and aspects of cognitive function in men with low levels.^82,86 In women, however, higher testosterone levels in older age appear to be associated with more rapid cognitive decline,⁸⁸ but this finding is complicated by other data suggesting testosterone replacement therapy may benefit cognitive function in the short-term in women whose ovaries have been surgically removed.⁸⁹ More research is needed to clarify the potential role of testosterone replacement on cognitive function in women.

Cortisol. Cortisol, a glucocorticoid hormone produced by the adrenal glands in response to HPA axis activation, is a critical moderator of the stress response. Cortisol also affects mood, attention, and memory, as well as immune, metabolic, and other physiologic functions.⁸² The HPA axis and resulting cortisol release are normally regulated by circadian signals; under healthy conditions, cortisol levels show a clear diurnal cycle, peaking in the morning and dipping at night.⁹⁰

In older adults, average cortisol levels are higher and the circadian rhythm of cortisol release is blunted. This may be partly related to diminished negative-feedback control over adrenal stimulation. Chronic or repetitive stress can add to persistent dysregulation of HPA axis signaling and cortisol release, and is linked to depression and anxiety, brain atrophy, cognitive impairment, and dementia.^82,90 Exercise and mindfulness training may help reduce stress, repair cortisol regulation, and slow cognitive decline.^90,91

Dehydroepiandrosterone (DHEA). DHEA is a precursor to other steroidal hormones such as estrogen, progesterone, and testosterone. In addition, DHEA has a range of direct hormonal actions. Most DHEA in blood is in the form of DHEA-sulfate (DHEA-S). DHEA is produced mainly in the adrenal glands, but smaller amounts are produced in the ovaries and testes. Levels of both DHEA and DHEA-S drop with age, such that levels in elderly individuals may be 80–90% lower than in younger individuals.^92,93 A large research review concluded higher blood levels of DHEA-S are associated with better cognitive performance in men and women.⁹⁴ Brain DHEA and DHEA-S concentrations are substantially higher than blood concentrations, and it has been proposed that DHEA may also be synthesized in the brain.^93,95 Preclinical evidence suggests DHEA may contribute to cortisol regulation, reduce neuroinflammation and brain oxidative stress, and promote neuronal growth.^93,95,96

Pregnenolone. Pregnenolone is upstream of DHEA; it gives rise not only to DHEA but also progesterone, cortisol, and other intermediary metabolites. The synthesis and metabolism of pregnenolone primarily takes place in the adrenals.⁵⁸⁸ Smaller amounts of pregnenolone are made in the gonads as well as the brain.^589-591 Similar to DHEA, pregnenolone declines with increasing age after reaching its peak around 20 years of age.⁵⁹² As compared with healthy controls, patients with Alzheimer disease tend to have lower levels of pregnenolone and its primary products in their brain.^593,594

Numerous studies have investigated the effects of pregnenolone in the brain.⁵⁹¹ Pregnenolone and its derivatives may enhance learning and memory, reduce dementia risk, and promote the growth and survival of brain cells.^595,596 Peripherally and in the brain, pregnenolone is metabolized to progesterone and further converted to allopregnanolone (ALLO-P).⁵⁹⁷ Pregnenolone, progesterone, and ALLO-P have been demonstrated to have neuroprotective effects.⁵⁹⁸ The action of ALLO-P as a gamma-aminobutyric acid (GABA) receptor agonist may contribute to pregnenolone’s central nervous system calming effects.^599,600 Pregnenolone and its metabolites have thus been considered as therapies for a variety of conditions associated with neuroinflammation and central nervous system hyperexcitability.^601,602

Memory formation and cognitive function rely on an appropriate balance of excitation and inhibition. Like DHEA, pregnenolone also exists in its sulfated form, pregnenolone-S, throughout the body, including in the brain.⁶⁰³ In contrast to ALLO-P, pregnenolone-S has GABA-inhibitory effects and as such may enhance processes such as memory formation.⁶⁰⁴ Pregnenolone-S mediates many aspects of synaptic plasticity; that is, the connections between neurons that are responsible for their communication, the learning of new skills, and formation of memory.⁶⁰⁵

Although there are currently no pharmacologic interventions specifically for age-related cognitive decline, medical approaches to underlying issues such as vascular disease and systemic inflammation may help prevent progressive cognitive loss. For example, the use of certain antihypertensive medications to lower high blood pressure may slow cognitive decline and prevent dementia; however, they also pose a risk of reducing cerebrovascular blood flow and causing more cognitive harm.^105,106

A number of observational studies have noted that patients using cholesterol-lowering drugs called statins (such as simvastatin [Zocor] and atorvastatin [Lipitor]) have a lower risk of mild cognitive impairment and dementia than those not using statins¹⁰⁷; however, other studies and case reports suggest statins may impair cognitive function in some individuals¹⁰⁸ and other studies have found no benefit.¹⁰⁹ Large randomized controlled trials have found statins had no impact on cognitive decline or dementia risk.^108,110-114

While once thought to hold promise for patients with mild cognitive impairment, it now seems that anti-dementia drugs, like the acetylcholinesterase inhibitors donepezil, galantamine (Razadyne), tacrine (Cognex), and rivastigmine (Exelon), have neither been shown to restore cognitive function nor protect against dementia in this population.^115,116 The use of biological and genetic markers in the future may help researchers identify those most likely to benefit from certain drug therapies.¹¹⁵

Several other medications with potential brain-protective effects are:

• Piracetam (Nootropil) and levetiracetam (Keppra) are anti-seizure medications sometimes used as cognitive enhancers. These and several related drugs (the “racetams”) are often colloquially referred to as “nootropics.” Preclinical evidence suggests these medications may reduce neuroinflammation, improve mitochondrial function, and prevent β-amyloid-induced neuronal dysfunction.^117-119 In early research, levetiracetam was found to improve cognitive performance on a memory test.¹²⁰ Findings from a clinical trial in cognitive impairment and dementia patients suggest piracetam may be most effective in those with depressive symptoms.¹²¹ Whether these medications hold benefits for patients with age-related cognitive decline and mild cognitive impairment has not yet been established. Also, the regulatory status of piracetam and related compounds is vague, and legal status varies between countries.
• Zileuton (Zyflo) is an inhibitor of the pro-inflammatory enzyme 5-lipoxygenase. While its main use is as an anti-asthma medication, zileuton has demonstrated some intriguing effects on brain function in preclinical trials. In animal research, zileuton has been found to reduce brain levels of β-amyloid and tau, as well as amyloid- and tau-related neuroinflammation, neuronal dysfunction, and cognitive impairment.^122-125 Other animal research suggests zileuton may reduce brain damage and cognitive losses after stroke.^126-128 The possible usefulness of zileuton in age-related cognitive decline, mild cognitive impairment, and dementia awaits future investigation.
• Hydergine, a mixture of ergot alkaloids (also called ergoloid mesylates), has been found to improve cognitive function and mood in preliminary trials in elderly subjects with age-related cognitive dysfunction.^129,130 Its mechanism of action is not completely understood; however, it appears to modulate neurotransmitter activity, improve cerebral metabolism, and increase antioxidant enzyme activity in the brain.^131,132 Despite interesting findings, there have been no clinical trials investigating hydergine’s usefulness in age-related cognitive decline and mild cognitive impairment for decades.
• Selegiline or deprenyl (Eldepryl) is a monoamine oxidase-B inhibitor that blocks the enzymatic breakdown of certain neurotransmitters, such as dopamine and serotonin. It is used to treat Parkinson disease, Alzheimer disease, and major depressive disorder, and is thought to have anti-aging effects.¹³³ Selegiline was found to improve cognitive performance in a six-month preliminary trial in human subjects with mild-to-moderate brain atrophy.¹³⁴ Studies in animals suggest it can reduce oxidative stress, protect against brain damage due to loss of blood flow, and preserve neurotransmission and memory.^135-138 More clinical trials are needed to ascertain the potential benefits of this medication in age-related cognitive decline.
• Centrophenoxine or meclofenoxate (Lucidril) enhances activation of cholinergic pathways in the central nervous system. An early trial in elderly subjects found centrophenoxine improved formation of new memory and increased subjective reports of mental alertness.¹³⁹ Animal research has found this medication may protect against cognitive losses due to aluminum toxicity,¹⁴⁰ drug toxicity,¹⁴¹ and lack of blood flow.¹⁴²
• Angiotensin receptor blockers (ARBs) (eg, candesartan [Atacand], telmisartan [Micardis]) are being examined for their ability to provide protection against cognitive impairment. The protective effect of candesartan on cognition was assessed in a randomized clinical trial of 176 participants aged 55 years or older with mild cognitive impairment and hypertension. Compared with the ACE inhibitor lisinopril (Zestril), one year of treatment with candesartan (up to 32 mg orally once daily) displayed superior outcomes on an executive function assessment.⁶⁰⁶ Both groups achieved similar blood pressures suggesting these results are independent of candesartan’s antihypertensive effects.
• Metformin is a widely used medication for type 2 diabetes that may reduce the risk of cognitive impairment. A retrospective study of 234 participants with type 2 diabetes found that long-term use of metformin (>6 years) was associated with a 55% reduced risk of cognitive impairment.⁶⁰⁷ Although clinical studies suggest metformin may maintain cognitive function and reduce the risk of developing dementia and Alzheimer disease in aged diabetic patients, its efficacy in nondiabetics remains unclear. However, animal studies suggest metformin treatment can improve cognitive function in old age by decreasing neuroinflammation, inhibiting mammalian target of rapamycin (mTOR) signaling, activating adenosine monophosphate-activated protein kinase (MAPK), and augmenting hippocampal autophagy to help maintain cognitive function.⁶⁰⁸ Additional studies in humans are required to clarify the effect of metformin on cognitive decline in nondiabetics.