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Health Protocols

Age Related Cognitive Decline

Healthy Brain: Integrative Approaches

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 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.241 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.242,243

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.244 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.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 0.2 mg of huperzine, 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. 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

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 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.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

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.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, 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.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

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 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.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, 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.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, only 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 HgbA1c), 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 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.307 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.309

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.310 Clinical trials in Alzheimer disease patients indicate melatonin may improve sleep, reduce behavioral symptoms, and enhance some aspects of cognitive function.311,312

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.313,314 Preclinical research shows 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 3 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 results from clinical trials is the presence of the ApoE4 gene variant, which is associated with disrupted DHA metabolism.331 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 micromoles per liter 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 in 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 in order 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 of 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 of 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 prior to 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 anticholinesterase 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 one year355 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

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 individuals361,362; 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 per day of marine phosphatidylserine to 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 per day of the phosphatidylserine supplement; 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. 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 An earlier clinical trial included 46 patients with mild-to-moderate Alzheimer disease. They were assigned to receive either 100 mcg colostrinin, 100 mcg selenium, or placebo in cycles of 3 weeks, followed by 2 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

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

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 grams, 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 cognitively normal elderly subjects. 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.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 900 mg, 600 mg, or 0 mg (placebo) per day of a high-rosmarinic acid spearmint extract for 90 days. Those receiving 900 mg performed better on memory tests and reported improved ability to fall asleep compared with those receiving placebo.414 In a pilot trial in 11 subjects with self-reported mild memory impairment, 30 days of treatment with 900 mg per day of a high-rosmarinic acid spearmint extract 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 culinary and medicinal mushroom from Asia. 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

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 oxidation-reduction (redox) biochemical reactions, through which it is converted to its reduced form, NADH. Redox reactions are important in cellular energy production in mitochondria. 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 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

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


Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the treatments discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. The publisher has not performed independent verification of the data contained herein, and expressly disclaim responsibility for any error in literature.

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