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. Animal research suggests ginkgo may stimulate neural stem cell proliferation and activity.
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. 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.
Bacopa
Bacopa (Bacopa monnieri), a plant with religious, cultural, and medical importance in India, has been used in traditional Ayurvedic medicine for centuries. 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. Human research suggests bacopa may also improve the stress response. Furthermore, in mice, bacopa extract increased brain levels of brain-derived neurotrophic factor (BDNF) and production of new neurons.
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. In one randomized controlled trial in 54 participants aged 65 years and older, those receiving 300 mg bacopa extract daily for 12 weeks had better cognitive performance and reduced symptoms of anxiety and depression after 12 weeks compared with those receiving placebo. Two clinical trials using different herb-nutrient combinations with bacopa have reported cognitive benefits from treatment with these supplements in older adults with mild cognitive impairment.
Huperzine A
Huperzine A is a biologically active compound from the Chinese medicinal herb Huperzia serrata. 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. Some anti-dementia drugs like donepezil also work by inhibiting acetylcholinesterase, and huperzine A has been proposed to have a disease-modifying effect in Alzheimer disease. 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.
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. Another meta-analysis of 20 randomized controlled trials in Alzheimer disease patients also noted likely benefits of huperzine A on cognitive function. 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 0.2 mg of huperzine, cognitive function and performance on task switching tests improved. 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.
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.
Acetyl-L-Carnitine
Acetyl-L-carnitine is a form of the amino acid, carnitine, produced in the mitochondria and involved in cellular energy production. 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. 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.
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. 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. 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. 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.
Magnesium-L-Threonate
Magnesium-L-threonate is a form of magnesium found to be particularly effective in raising brain magnesium levels. Increasing brain magnesium levels enhanced neuroplasticity and improved cognitive function in research animals. Supplementation with magnesium-L-threonate has been shown to prevent age-related loss 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. 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.
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 reason for its cognitive benefits. 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. Another study in 447 older adults with increased cardiovascular risk also noted better cognitive performance in those with greater urinary polyphenol concentrations. In addition, intakes of specific polyphenol-rich foods (olive oil, coffee, walnuts, and wine) were independently linked to better performance on tests of certain aspects of cognitive function.
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.
Berry polyphenols. Blueberries and their polyphenols, especially the anthocyanins that give them their color, may have preventive effects against chronic diseases including cognitive disorders. 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. In a randomized controlled trial on 37 people between 60 and 75 years old, taking 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. Another controlled trial found 24 weeks of treatment with whole-fruit blueberry powder improved cognitive function in elderly adults. In a placebo-controlled trial in 26 patients, taking 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.
Grape polyphenols. Grape polyphenols, such as quercetin, lycopene, resveratrol, and anthocyanins, have demonstrated neuroprotective actions. 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. 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. 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. 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, only in those with the lowest cognitive test scores at baseline.
Resveratrol. Resveratrol is a grape polyphenol found especially in red wine and shown in numerous studies to have powerful free radical-quenching capacity. Resveratrol appears to slow cognitive decline through regulating age-related signaling, improving cerebral blood flow, and increasing neuroplasticity. 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.
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 HgbA1c), increased neuronal connectivity, and decreased body fat. 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. 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.
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. A review of 21 studies found green tea may reduce anxiety, benefit memory and attention, and enhance brain function.
Chlorogenic acids. Chlorogenic acids are polyphenols found in coffee, and many studies have linked chlorogenic acid consumption to better cognitive function and mood. 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.
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. In older individuals, lower nighttime melatonin levels have been correlated with mild cognitive impairment and dementia. Animal studies suggest melatonin can repair circadian and sleep disturbance and reduce associated cognitive problems. Melatonin’s potential to reduce neuroinflammation and neurodegeneration have also been noted in animal models of both Alzheimer and vascular dementia.
In a controlled trial, 61 patients with mild cognitive impairment received melatonin, in doses of 3‒24 mg at bedtime, in addition to their usual medications, and 35 patients received usual treatment alone. Participants were monitored for 15–60 months. At the end of the trial, the melatonin-treated group had improved sleep, mood, and performed better on all tests of cognitive function. In a previous trial with a similar design, 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 An open trial in 10 participants with mild cognitive impairment found 6 mg of melatonin nightly for 10 days improved sleep quality, reduced depressed symptoms, and increased performance on a memory task.
A randomized controlled trial in 139 elderly participants undergoing hip joint surgery found 1 mg of melatonin taken before bedtime for six days beginning one day before surgery prevented postoperative cognitive decline. Sleep quality, fatigue, and general well-being were also better in those receiving melatonin compared with placebo. Clinical trials in Alzheimer disease patients indicate melatonin may improve sleep, reduce behavioral symptoms, and enhance some aspects of cognitive function.
Omega-3 Fatty Acids and 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. Preclinical research shows DHA plus eicosapentaenoic acid (EPA), another omega-3 fatty acid from fish, may protect against amyloid plaques and neurofibrillary tangles, 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. In addition, DHA has anti-inflammatory effects and is a precursor for neuroprotectin D1, a signaling molecule involved in neuronal growth and survival.
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. 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. 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.
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. Similarly, a large review of 24 studies found evidence suggesting a beneficial effect of omega-3 fatty acid intake on cognitive aging. 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 subjects; 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.
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 3 years. Although DHA plus EPA supplementation did not affect cognitive function in the initial analysis, 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. 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.
Another factor that may influence results from clinical trials is the presence of the ApoE4 gene variant, which is associated with disrupted DHA metabolism. One study in 915 elderly participants only noted a link between higher seafood consumption and reduced cognitive decline in ApoE4 carriers. 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. Because of such findings, it has been proposed that DHA supplementation may be more important in carriers of ApoE4.