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. 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.
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. 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. 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. 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.
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. 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.
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. 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).
Acetylcholine precursors, alone or in conjunction with acetylcholinesterase inhibitor drugs, are a promising approach to dementia treatment. 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. 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. Another pilot trial found α-GPC had beneficial effects on cognitive function after 15 days of treatment in patients who had experienced stroke.
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 year and two years, and reduced apathy, the loss of motivation associated with progressive dementia, after three years. The most recent report from this trial showed co-treatment with these two agents reduced Alzheimer-related behavior and mood disorders.
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.
Early clinical trials using phosphatidylserine extracted from bovine brain tissue showed promising cognitive benefits in elderly individuals; 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.
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. 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. 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.
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. 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. 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.
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. 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. 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. Studies have reported mild side effects that resolve quickly in some patients treated with colostrinin.
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. 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. Other studies using oral vinpocetine have noted its ability to improve cognitive performance in patients with mild cognitive impairment as well as cerebrovascular insufficiency. 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. 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. 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. In addition, animal and laboratory research suggests chronic low-dose lithium treatment can increase neuronal production of BDNF.
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. 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.
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. 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.
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).
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.
Rosmarinic acid has shown neuroprotective effects, such as reducing neuroinflammation and brain oxidative stress and preventing β-amyloid-induced cognitive decline, in laboratory models. Rosmarinic acid also appears to inhibit an enzyme involved in tau protein pathology. 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.
In a randomized placebo-controlled trial, 90 individuals with age-related memory impairment received either 900 mg, 600 mg, or 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. 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.
Green Oat Extract
Oat (Avena sativa) is a cereal grain with many active compounds. An extract from wild green oat has been shown to inhibit an enzyme called monoamine oxidase-B (MAO-B). 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. Blocking MAO-B helps normalize dopamine levels, which may reduce oxidative stress and improve aspects of cognition and memory. Wild green oat extract has also been found to dilate cerebral blood vessels and inhibit another enzyme called phosphodiesterase-4, an effect that may slow age-related cognitive decline.
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. 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.
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. 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. 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.
Pyrroloquinoline Quinone
Pyrroloquinoline quinone, or PQQ, is a vital compound that supports growth and development. 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. 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. A number of studies also show PQQ may prevent the accumulation of β-amyloid. Furthermore, PQQ has been found to stimulate the production of a protein called nerve growth factor, promote regeneration of nerve cells,447,448 and preserve cognitive function in laboratory animals.
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. Another study similarly noted that taking 20 mg PQQ daily for 12 weeks increased regional brain blood flow and oxygen utilization in healthy subjects.
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. 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.
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. It is thought that raising NAD+ availability may contribute to slowing the aging process and preventing age-related diseases.
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. In mice, administering oral nicotinamide riboside has been found to increase cerebral NAD+ levels and improve cognitive function, enhance neuroplasticity, and reduce tau protein-induced neuronal damage. Further evidence from animal studies suggest NAD+ therapy could possibly stimulate mitochondrial activity, maintain the regenerative potential of stem cells, and extend lifespan.
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. Lower blood levels of CoQ10 have been correlated with increased risk of disabling dementia in older individuals and worse cognitive function in heart failure patients. Preclinical evidence suggest CoQ10 may slow cognitive decline in patients with neurodegenerative diseases like Huntington, Parkinson, and Alzheimer disease.