Age Related Cognitive Decline
Psychological Risk Factors Contributing to Cognitive Decline
There is a tendency to focus on the biological aspects of a disease state because they are perceived as tangible, measurable, and modifiable. However, more loosely defined facets of our lives related to our psychological condition contribute to our mental fluency as well. The ways in which the brain is utilized and stimulated impact its functional state at all ages.
Psychoanalytical tests have found that cognitive impairment is closely correlated with traits such as boredom-proneness, loneliness,123 small social network,124 and high stress.125
Anxiety and Stress
Research in patients with anxiety has shown that, compared to non-anxious control subjects, those with high-anxiety levels must exert greater effort (dedicate more brain resources) to maintain the same level of performance on cognitive tests.126 More severe anxiety is also predicative of earlier conversion from mild cognitive impairment to Alzheimer’s disease.127 In men, even subclinical (low-level) anxiety is tied to cognitive impairment.128
Excessive stress leads to cognitive dysfunction as well. In a study involving 36 women between the ages of 25 and 53, those with the highest work-related stress levels displayed decreased attention and visuo-spatial memory.129 Likewise, in a cohort of 811 aging men, subjects reporting higher stress levels scored lower on the Mini-Mental State Examination than their low-stress counterparts. This indicates that “psychological stress had an independent inverse association with cognition…”130
Posttraumatic stress disorder (PTSD) is a condition characterized by chronic, lingering anxiety and stress related to a traumatic event in the past. A comprehensive review of eight studies highlighted a strong association between PTSD and smaller brain size (total brain volume).131 The duration of PTSD influences the extent to which the brain deteriorates; developing effective coping strategies as soon as possible may help to limit PTSD-induced decreases in brain volume.132
Meditation is an effective method for relieving stress. With the connection between stress and cognitive dysfunction in mind, researchers studied the effects of an 8-week audio-guided meditation program on cerebral blood flow and cognition in 14 subjects with memory problems. Tests revealed that meditation significantly increased cerebral blood flow in several major brain regions. Improvements in tests of verbal fluency and logical memory were attributed to meditation as well.133
An intimate relationship exists between depression and cognitive dysfunction. Many studies have closely examined this link and allude to the intertwinement of these two conditions, rather than a causal effect of one on the other. Interestingly, depression seems to worsen cognitive dysfunction, but poorer cognitive health predisposes aging individuals to depression as well.134
In fact, studies designed specifically to assess age-related cognitive performance in depression show an interrelationship between the two conditions. A group of aging subjects diagnosed with depression completed various cognitive tests and their results were compared to those of age and sex – matched, non-depressed control subjects. More than half of the depressed subjects scored below the 10th percentile of the control group on the battery of tests they completed. The conclusion drawn from this evidence was that “late-life depression is characterized by slowed information processing, which affects all realms of cognition.”135
Continuing research has lead to the delineation of “depression-associated reversible dementia,” which is cognitive impairment associated with depression that subsides upon improvement of depression. Nonetheless, in a study of 57 elderly subjects with major depression, those who displayed depression-associated reversible dementia were nearly five times more likely to develop true dementia over a roughly three-year period.136
Several cognitive and neuropsychological deficits accompany depression, including impairments in executive function, attention, episodic memory, visuo-spatial skills and information processing.137 Other research indicates that deterioration in structural integrity of specific brain regions involved in emotional processing is observed in depressed patients.138
Social Network and Personal Relationships
Several studies have suggested that maintaining a large network of friends and other personal relationships, and regularly engaging in social and productive activities is associated with a decreased risk of cognitive decline.139,140 Conversely, social disengagement, defined as having very few or no social relationships, is a strong risk factor for cognitive decline.141
Among 2,249 women aged 78 or older, those with smaller social networks at baseline had a significantly greater chance of having developed dementia within one year than women with larger social networks. The investigators stated that “our findings suggest that larger social networks have a protective influence on cognitive function among elderly women.”142 In another study, researchers assessed work history data for nearly 1,000 subjects, who were then followed for up to six years. Participants in the study whose careers involved regularly working closely with people on complex tasks were much less likely to develop dementia over time than subjects who did not regularly work closely with other people.143
Sixteen behavioral measures were correlated with Mini-Mental State Examination (MMSE) scores for 1,437 elderly subjects in an Austrian study. Among other measures, living alone and perceiving life as being generally stressful were independently associated with lower MMSE scores.144 These findings are supported by a separate study that identified being unmarried as an independent risk factor for cognitive impairment in over 7,000 Italian subjects.145
Social integration, defined by marital status, volunteer activity, and frequency of contact with children, parents, and neighbors, conveys a memory preserving effect in elderly adults. Over a six-year period, memory among those with the lowest level of social integration declined at twice the rate of subjects with the higher levels of social integration.146
Maintaining close ties with friends and loved ones, and being involved in various group-oriented activities, especially outdoors, is an effective method for stimulating and maintaining your brain as you age.
Mental and Physical Activity
The brain consists of a vast network of approximately 90 billion (109) neurons interconnected by 1,000 trillion (1015) synaptic junctions.147 Each mental and physical task that we perform stimulates this massive network in a unique way. Regular stimulation of diverse synaptic pathways by engaging in a wide range of mentally and physically challenging activities directly influences our ability to learn by enhancing synaptic plasticity, and initiating the process of neurogenesis in critical areas of the brain.148,149 In fact, it is now clear that neural plasticity allows the structure and function of the adult human brain to change significantly as a result of new experiences.150
Physical Activity and Brain-Derived Neurotrophic Factor
A critical driving force behind neural plasticity (and therefore overall cognitive function) is a protein called brain-derived neurotrophic factor, or BDNF. BDNF acts upon areas of the brain involved in learning, memory, and higher-order thinking to stimulate genesis of new neurons, survival of existing neurons, and synaptic adaptation.151,152,153 Low levels of BDNF are observed in a variety of brain disorders, including cognitive decline, depression, dementia, and Alzheimer’s disease.154,155
Physical exercise is known to enhance cognitive function in humans and other animals, and many researchers now believe that an increase in levels of BDNF induced by exercise mediates this improvement.156,157,158 Several studies have demonstrated that moderate to high intensity aerobic or anaerobic exercise induces sharp (intensity-dependent) increases in BDNF levels in humans.159,160
Gold et al noted a marked increase in serum BDNF levels induced by a 30-minute bout of moderate intensity cycling; this was observed in both healthy subjects and in patients with multiple sclerosis.161 These findings are supported by Tang et al who found that only 15 minutes of a high-intensity stair climbing exercise significantly bolstered serum BDNF levels in healthy men.162 At the highest intensity level, exercise induces sharp increases in serum BDNF levels in as little as three minutes, as reported by Winter et al, who documented the effects of very-high intensity sprinting exercises in healthy young men.163 In this last study, the post-exercise spike in BDNF levels corresponded with a 20 percent improvement in short-term memory.164
Animal models allow scientists to more closely study the dynamic effect of physical activity on the brain. Work conducted by researchers in Taiwan indicates that, while both leisurely (voluntary) physical activity (ie. briskly walking in the park) and targeted physical exercise (ie. going to the gym) boost levels of BDNF and enhance plasticity in animals, they do so in different regions of the brain.165 These findings highlight the importance of not only engaging in exercise routines, but leading a generally active lifestyle as well in order to promote overall brain health.
The beneficial effects of exercise on brain health appear to be limited only by the duration of exercise. Studies conducted in rats reveal a direct correlation between the amount of time spent exercising (wheel running) and the genetic expression of BDNF. In other words, the longer the rats exercised, the more robust the increase in BDNF gene expression.166
The protective effects of regular exercise on cognitive health were documented in a recent comprehensive analysis of 15 studies including over 33,000 subjects who were followed for up to 12 years. Individuals with the highest levels of physical activity were a striking 38% less likely to show signs of cognitive decline over time compared to those with very-low activity levels. Amazingly, even low to moderate levels of physical activity conveyed a robust 35% reduction in risk for cognitive decline. The importance of physical activity for brain health was reflected in the authors’ concluding statements: “the present results suggest a significant and consistent protection for all levels of physical activity against the occurrence of cognitive decline.”167
Mental Activity, Brain Plasticity, and Cognitive Reserve
Neural plasticity, the dynamic ability of the brain to adapt and respond to novel stimuli in a unique and reinforceable way, is a pivotal aspect of cognition. Plasticity serves as a key medium for the effects of practicing a physical activity – i.e. getting better at a physical task over time. As we practice an activity repetitively signals are transmitted through the brain in a specific pattern over and over again. This redundant signaling ultimately strengthens the connections between neurons in the signaling pathway required to execute the task, leading to greater efficiency and accuracy of signal transmission.
An important limitation of physical practice, though, is that improvements in ability are generally confined to the task being practiced. In other words, practicing tennis does not increase proficiency in bowling. Repetitive mental stimulation, on the other hand, exerts domain-wide improvements that impact other tasks as well. To elaborate, practicing a mentally challenging activity that requires utilization of higher-order cognitive processes, playing chess for example, can improve fluency in other activities that require similar cognitive processes, like driving a vehicle.168,169
Brain plasticity also serves as a prerequisite for a more global effect known as cognitive reserve. This phenomenon arises from, and is dependent on, synaptogenesis – the formation of new synapses, the hallmark physical affect of mental training.
The introduction of novel cognitive stimuli encourages the brain to establish new neural networks through synaptogenesis, which can then be used to bypass breakdowns in other neural networks arising from age-related or pathological deterioration in brain circuitry.
Cognitive reserve is measurable as a function of life experiences and studies have shown that cognitive reserve scores correlate with overall cognitive function in an aging population.170 In subjects with Alzheimer’s disease or mild cognitive impairment, higher cognitive reserve mitigates the loss of function typical with these conditions.171 This same study found that individuals with higher cognitive reserve scores performed better on assessments of visuo-spatial ability than those with lower scores, despite presenting with equal pathologic progression of Alzheimer’s disease or mild cognitive impairment as assessed by brain imaging.
Just as the desire to maintain a fit and functional body into late life necessitates regular physical exercise, ensuring cognitive dexterity with advancing age requires constantly pushing the brain to new limits in order to evoke plastic changes that strengthen existing, and encourage new, synaptic connections. This becomes clear when considering that individuals with mentally demanding careers appear to be at significantly decreased risk of developing Alzheimer’s dementia in later life, compared to those whose careers centered on physical labor.172
Plasticity is an intrinsic property of the brain maintained throughout life; and so cognitive stimulation and training enhance cognitive reserve and convey protection against loss of brain function regardless of age.173 In a study including nearly 500 individuals with clinical cognitive impairment, computerized cognitive training significantly improved several measures of cognitive function.174 Improvement was still evident up to three months post training in some cognitive assessments. Moreover, as little as two hours of cognitive training initiates structural changes in the brain suggesting that those who chose to challenge their intellectual capacity reap the benefits instantaneously.175
A 2005 case study of a chess player reveals the true compensatory ability of the brain given regular cognitive stimulation. The chess player, an aging gentleman whom heretofore displayed excellent cognitive function, presented with complaints of slight memory loss, which over the next two years progressed into mild cognitive impairment. The man then fell ill with an unrelated illness and passed seven months later. The autopsy revealed that he had been living with advanced Alzheimer’s pathology in his brain, which would normally cause severe deterioration of cognitive ability. Remarkably, the man displayed only mild cognitive impairment until his death.176 Regularly playing chess had imbued the gentleman with a great deal of cognitive reserve, allowing for relatively normal neural efficiency despite stark deterioration of the structural integrity of the brain.
Speaking more than one language is also a strong inducer of plasticity and cognitive reserve. Learning a second language requires the brain to constantly categorize information in ways that are unnecessary when only a single language is spoken; this establishes numerous new neuronal communication streams. In a study of more than 200 individuals clinically likely to have Alzheimer’s disease, being bilingual was found to delay that onset of symptoms by over five years, and delay diagnosis by nearly four and a half years relative to monolingual speakers.177
Cognitive stimulation and training also benefit the brain by enhancing cerebral blood flow. Mozolic et al have shown that an eight-week attention and distractibility cognitive training program significantly increased blood flow to the prefrontal cortex, a brain region involved in personality expression and decision making. The control group in this study, who were exposed to education material, but not intensive cognitive training, displayed no increase in cerebral perfusion.178
A lifestyle incorporating frequent physical exercise, continual learning, and regular cognitive stimulation is likely to be the most effective means for preserving, and possibly enhancing, cognitive function at any age.
Medical Approaches to Combating Cognitive Decline
While various pharmacologic therapeutics have been studied in hopes of identifying an effective intervention for preserving cognition with aging, and preventing diseases of the brain such as Alzheimer’s disease, evidence in support of medical therapies are equivocal at best.179 However, preliminary data suggests that some drugs may provide limited benefits for brain health, and thus may adjunctively synergize with increased mental and physical activity levels, dietary changes, and neutraceutical options to optimize brain function with advancing age.
Piracetam has been studied in a wide-range of patient populations, and has demonstrated small benefits in a variety of models of neurological disorders. Multiple mechanisms for the observable effects of piracetam on brain function have been proposed, though a precise description of its mechanism(s) of action has yet to be elucidated. Preliminary studies suggest that piracetam may modulate the signaling of multiple neurotransmitter receptors,180 and improve neuronal membrane fluidity.181
A recent comprehensive review which assessed the efficacy of piracetam in older subjects suggests that the drug may provide appreciable benefits for cognitive dysfunction. The reviewers concluded that “…the results of this analysis provide compelling evidence for the global efficacy of piracetam in a diverse group of older subjects with cognitive impairment.”182
Like piracetam, hydergine has been proposed to affect the brain in multiple ways. The drug, which largely fell out of clinical use decades ago after it was shown to be largely ineffective for Alzheimer’s disease, is still incorporated by some integrative physicians into regimens for brain support. Proposed mechanisms include enhancing brain glucose utilization,183 increasing acetylcholine signaling,184 and preserving hippocampal structure with advancing age,185 among others.
Collectively, data indicates that hydergine may be slightly more effective than placebo for treating dementia; however, a review concluded that “the efficacy of Hydergine remains inadequately defined.”186
Deprenyl, in low doses, is a selective MAO-B inhibitor, and thus slows the breakdown of various neurotransmitters in the central nervous system, especially dopamine, so it may enhance mood and energy.187 The drug has been shown to preserve some regions of the rodent brain with increasing age,188 and to ameliorate HIV-related cognitive impairment in a double-blind, placebo-controlled human trial.189
Centrophenoxine is structurally related to dimethylethanolamine (DMAE), a metabolic precursor to acetylcholine. It has been shown that centropehnoxie increases acetylcholinergic synaptic signaling,190 and improves memory and mental alertness in healthy elderly subjects.191 Other proposed mechanisms by which centrophenoxine may benefit brain function are improving neuronal hydration through enhanced membrane fluidity,192 and the ability to reduce neuronal oxidative stress.193
Dietary Considerations for a Healthy Brain
The exceptionally high rate of metabolism in the brain makes it particularly responsive to the nutritional content of the diet. A Western dietary pattern, typified by excess consumption of simple carbohydrates and dietary fat (in particular saturated fat and omega-6 polyunsaturated fatty acids), is a detrimental, yet alterable, modulator of cognitive function. Numerous studies have identified high intakes of simple sugars and saturated fats as being especially deleterious for brain health.194,195,196 Transitioning to a slightly calorie-restricted Mediterranean diet high in mono- and poly- unsaturated omega-3 fats, fiber, and polyphenols will provide the brain with nutrition to function at high capacity and efficiency.
Some dietary considerations that may be easily overlooked provide substantial brain benefits as well.
Calorie restriction is the restriction of caloric intake to a level modestly below normal, typically 20% to 30% less, but the diet should be dense with micronutrients to maintain optimal nutrition. Caloric restriction is well-known for its ability to induce favorable changes in peripheral insulin sensitivity, which enhances insulin signaling in the central nervous system. The brain relies heavily on proper insulin signaling for a variety of functions that impact cognition, and so it is not surprising that caloric restriction has been shown to benefit cognitive function in many animal and human studies.197,198
A study conducted in 124 hypertensive individuals who led generally sedentary lifestyles found that four months of caloric restriction in conjunction with a diet designed to help control blood pressure produced several neurocognitive improvements in domains including executive learning and psychomotor speed.199
Caloric restriction also boosts levels of several neurotrophic factors, including BDNF, and thus creates an ideal environment for plastic adaptation of the brain in response to mental stimulation.200
A great deal of scientific literature validates the Mediterranean diet as a staple for those concerned with cardiovascular health, cognitive health, and longevity. The diet centers on “good” fats – mono- and poly-unsaturated fats, especially omega-3’s and olive oil, multi-colored fruits and vegetables, and moderate red wine consumption.201,202 Adherence to the Mediterranean diet has been linked with improved insulin sensitivity,203 lipid metabolism204, blood pressure,205 reduced risk of developing cancer206 or metabolic syndrome,207 as well as an overall decrease in mortality.208, 209
The brain also benefits greatly from the health-promoting lipids and antioxidants that are ample in the Mediterranean diet.210 An abundance of scientific literature concedes that adherence to the Mediterranean diet is associated with better cognitive performance in a variety of populations.211
In 1,393 individuals participating in a prospective study with follow up of 4.5 years, greater Mediterranean diet adherence was shown to decrease the risk of developing mild cognitive impairment by 28% compared to lesser adherence. Additionally, in those who consistently consumed a Mediterranean diet, but did develop mild cognitive impairment, risk of converting to Alzheimer’s disease was cut by 48% relative to subjects whose diet deviated from the Mediterranean style.212 Several additional studies have concluded similarly.213,214,215
Moderate Alcohol Consumption
While there is no question that heavy alcohol consumption is deleterious to nearly all aspects of health, including cognition, moderate alcohol consumption, characterized as two drinks daily, seems to convey protection against cognitive decline with aging. Fifteen studies were summarized in a recent comprehensive review which included data for over 36,000 subjects; those classified as “moderate” drinkers were roughly 25 – 30% less likely to develop Alzheimer’s disease, vascular dementia, or any-type dementia, than non drinkers or heavy drinkers.216
Light to moderate alcohol consumption during midlife appears to convey protection against cognitive decline in late life. A study following over 1,400 individuals for nearly 23 years found that mid-life moderate drinkers were less likely to display signs of cognitive impairment later in life than their teetotaling and heavy drinking peers.217
Evidence suggests that red wine may be the alcoholic beverage of choice for maintaining cognitive health, as it contains many phenolic antioxidant compounds that are suspected to impede the pathological progress of Alzheimer’s disease,218 and limit the neurological consequences of high cholesterol.219 Indeed, a seven-year longitudinal study including over 5,000 healthy subjects found that those who regularly drank a moderate amount of red wine scored better on every test of cognitive performance that the investigators administered than non-drinkers.220 Other studies have produced similar findings.221
Many of the benefits of moderate drinking are likely attributable to alcohol’s profound positive impact on levels of HDL (“good”) cholesterol and enhancement of cholesterol efflux.222,223,224 Alcohol consumption protects against cardiovascular and neurological disease and degeneration via mechanisms that may be thought of as hormetic (stress adaptive) in nature; the concluding statements of a recent review on this topic suggest that “to a certain extent, moderate alcohol exposure appears to trigger analogous mild stress-associated, anti-inflammatory mechanisms in the heart, vasculature, and brain that tend to promote cellular survival pathways.”225
Moderate Caffeinated Coffee Consumption
Coffee, like red wine, is an excellent source of antioxidant and neuroprotective compounds.226,227,228,229 However, it has been suggested recently that the antioxidant compounds in coffee may synergize with caffeine to enhance the protective effect against brain pathology, and that decaffeinated coffee does not provide the same level of neuroprotection observed with caffeinated coffee.230 Accordingly, a study which followed nearly 700 elderly men for a 10-year period revealed that coffee consumption, roughly equivalent to three cups daily, was associated with a 4.3 fold slower rate of cognitive decline when compared to those subjects who did not drink coffee.231
A team of Scottish researchers recently found that coffee consumption was tied to superior reading ability and higher scores on some other cognitive assessments in a cohort of over 900 healthy adults.232
Moreover, a level of evidence that is strongly suggestive has accumulated indicating that caffeine itself exerts a variety of protective and augmentative effects in various cognitive domains.233,234,235,236 Animal models have identified several mechanisms by which caffeine protects the aging brain, including preservation of blood-brain barrier integrity and suppression of brain and plasma amyloid-beta levels.237,238,239
In addition to preserving cognition, coffee consumption may also protect against type 2 diabetes and some cancers.240,241 Black coffee or espresso appear to be superior choices when selecting a coffee beverage for health benefits, since adding sugar or non-dairy creamer has been shown to blunt the ability of coffee to increase the levels of antioxidants in circulation.242
Nutraceuticals to Support Brain Health
Healthy dietary habits ensure that food is an excellent source of nutrients that serve to support the brain both structurally and functionally. However, optimal neruoprotection and cognitive preservation often require micronutrient intakes in excess of those obtainable in a typical Western diet, or intake of specialized nutrients not common in most foods.
Many nutrients known to modulate physiological process important for brain health have been shown to slow cognitive deterioration, or enhance mental performance.
Phospholipids are an integral component of all cells in the body, without which the integrity of cell membranes would fail, as would cellular function. In the brain omega-3 fatty acids are incorporated liberally into cellular phospholipid bilayers; DHA alone accounts for 40% of the phospholipid content of neuronal membranes.243 Along with EPA, DHA plays a central role in neurotransmitter signaling and synthesis, and together the omega-3 fatty acids modulate numerous aspects of cognition and behavior.244,245,246
Evidence suggests that the typical Western diet is severely deficient in beneficial omega-3’s, and supplies omega-6’s in excess, which creates a fatty acid milieu that promotes inflammation and contributes to several age related degenerative diseases.247 Numerous studies have concluded accordingly, indicating that supplementation with omega-3 fatty acids optimizes cognitive health.
Slightly less than two grams of fish oil daily, over a 24-week period, was shown to significantly improve scores on a standardized assessment of cognitive function in subjects with mild cognitive impairment. Increases in red blood cell EPA confirmed that supplemental fish oil was biologically available and responsible for the improvement in cognition.248 A similar, but longer-term, study involving nearly 1,500 subjects found that daily omega-3 supplementation was independently associated with a dramatic reduction in cognitive decline over a 1.5 year period in an aging study population, compared to those not taking omega-3 supplements. Importantly, this study also found that dietary fish consumption was not associated with cognition, while omega-3 supplements were, highlighting the superiority of supplementing with omega-3’s for supporting brain health.249
In addition to the numerous studies that have associated increased dietary omega-3 intake with better cognitive performance,250,251 a more detailed study confirms the principle role the role of DHA in mediating this improvement. Researchers assessed serum phospholipid levels in 280 middle-aged (35 – 54) healthy study volunteers, which were then correlated to cognitive function. It was found that subjects with the highest serum levels of DHA performed significantly better in multiple domains of cognition than their cohorts with lower DHA levels. This association remained significant even after adjustment for various other confounding factors.252
Wild Green Oat Extract
By age 45, the brain’s levels of dopamine begin to diminish.352 This not only makes people feel older, but is also involved in accelerated brain aging.
Dopamine depletion is largely caused by rising levels of the MAO-B enzyme. The ensuing dopamine deficiency strikes the brain’s signaling system. The tragic result is cognitive decline, destruction of brain cells, reduction of youthful vigor/sexual desire, progression toward Parkinson’s/neurological disorders, and a decreased lifespan.353-358
In a search for a safe method to block the insidious MAO-B enzyme, scientists have identified a bioactive extract of wild green oat that not only inhibits MAO-B and the resulting breakdown of dopamine, but enhances dopaminergic neurotransmission that normally declines with aging. These protective actions enable more dopamine availability for use by brain cells.
In human studies, the effects of wild green oat extract resulted in increased focus and concentration, processing speed, executive function, and working memory as well as other parameters of enhanced dopaminergic transmission.359,360
The discovery of the specific actions of wild green oat extract represents a significant advance in the technology of age management. It provides a method for halting some of the most destructive aspects of neurological aging, thus helping improve cognitive function and enhancing the quality of life.361 Moreover, preclinical studies have shown that the well-known anti-aging drug deprenyl can extend the lifespan of some animals.358,362-365
Polyphenols and Anthocyanins
The disproportionately large metabolic demand of the brain compared to other parts of the body gives rise to an environment in the CNS primed for generation of cell-damaging oxygen free radicals. Polyphenolic antioxidants, such as resveratrol from grapes, catechins from green tea, and anthocyanins from blueberries are among the strongest naturally occurring free radical neutralizers, and several laboratory in vitro studies have confirmed the neuroprotective properties of these antioxidants. In the past, some scientists questioned the utility of these compounds in protecting neural health in vivo due to concerns over oral bioavailability. However, data clearly indicates that these protective compounds are not only adequately bioavailable ingested orally, but accumulate in the brain after oral ingestion, indicating blood-brain barrier permeability as well.253,254,255,256,257
Blueberries. Multiple animal studies have provided mechanistic insights into the well-documented brain health benefits of blueberry constituents. In addition to strongly attenuating neural oxidative stress, blueberry components also inhibit acetylcholineesterase (AChE), an enzyme responsible for catabolizing the important neurotransmitter acetylcholine, thus preserving acetylcholine-related memory and learning.258 Blueberry supplementation also stimulates neurogenesis and enhances neuronal plasticity (adaptability) in the hippocampus, the region of the brain chiefly affected by Alzheimer’s disease.259 Other research has revealed that blueberry compounds may optimize cognitive performance through modulation of genetic expression within the brain.260
These biochemical actions translate into observable improvements in learning, memory, and overall cognitive performance resultant from blueberry supplementation or dietary fortification in both animal and human studies.261,262,263
Other beneficial effects of blueberry consumption include enhanced insulin sensitivity in obese subjects,264 and improved vascular smooth muscle contractility after prolonged supplementation.265
Tea Polyphenols. Interest in studying components of tea in the context of brain health was generated by publication of epidemiological evidence which linked increased tea consumption with superior cognitive function in aged populations.266,267 Investigations were fruitful in that they led to the elucidation of powerful tea constituents, including epigallocatechin-3-gallate (EGCG), and other phenolic antioxidants, and findings that these compounds possess tremendous disease modifying potential in Alzheimer’s disease and the ability to preserve cognition in healthy aging individuals, and animals.268,269,270
In a double-blind placebo-controlled trial, co-ingestion of green tea polyphenols and L-theanine, an amino acid found in tea, was shown to improve memory and attention in subjects with mild cognitive impairment. Those subjects who consumed the supplement also displayed significantly increased theta brain wave activity as measure by electroencephalography (EEG); theta waves are associated with learning and memory.271,272,273 Similar results were observed in animal models of cognitive impairment, and researches attributed some of the benefits to the free radical scavenging ability of green tea polyphenols.274,275 Other research has shown that daily green tea supplementation attenuates age-related cognitive dysfunction in mice, even when treatment is initiated well into adulthood. These results suggest that green tea might protect neurons and preserve cognition regardless of age.276
Tea polyphenols and theanine may also ameliorate the damaging effects of amyloid-beta proteins, which accumulate in the brain as the hallmark pathology of Alzheimer’s disease causing severe oxidative stress and neuronal death. Several animal studies have found that EGCG and related catechins suppress amyloid-beta induced cognitive dysfunction and neurotoxicity.277,278,279
Green tea supplementation has also been shown to optimize insulin signaling280 and endothelial function,281 which may provide additional neuro-protective benefits. Additional clinical trials have established that daily green tea supplementation favorably modulates multiple other metabolic parameters related to brain health, including body weight and lipid peroxidation.282
Resveratrol. Many researchers believe that at least some of the health benefits of red wine consumption may be due to its modest content of the well-known phenolic antioxidant molecule resveratrol. In addition to a multitude of evidence suggesting that resveratrol extends lifespan in experimental settings, likely by mimicking the genetic effects of calorie restriction,283 numerous publications also highlight various roles for resveratrol in optimizing brain function.
Resveratrol may benefit the brain via mechanisms including increased synthesis of the growth factors IGF-1284 and BDNF285 in the hippocampus, suppressing formation of inflammatory metabolic products within the brain,286,287 reinforcing the integrity of the blood-brain-barrier,288 and optimizing overall brain metabolism.289 Other studies have shown that resveratrol supplementation preserves cerebrovascular integrity with aging,290 and protects the brain after traumatic brain injury as well.291
In a double-blind, randomized, placebo-controlled human clinical trial, doses of resveratrol ranging from 250 – 500 mg were shown to dose-dependently enhance cerebral circulation and brain oxygenation.292 In a trial involving non-human primates resveratrol supplementation was shown to increase physical activity levels and enhance both working and spatial memory. The investigators concluded that “these results suggest that resveratrol could be a good candidate to mimic long-term CR effects and support the growing evidences that nutritional interventions can have beneficial effects on brain functions even in adults.”293
Inside the central nervous system B-vitamin-dependent reactions are responsible for ensuring the proper function of a vast array of neurochemical processes. When levels of B-vitamins, especially B6, B12, and folic acid, are insufficient to optimally support these reactions consequences such as impaired neurotransmitter synthesis and neurocapillary-damaging hyperhomocysteinemia can result.294
|Figure 3: A mitochondrion; organelle within the cell within which chemical energy in the form of ATP is produced.|
Multiple human studies have associated low plasma levels of B-vitamins, and even subclinical deficiencies, with cognitive decline and dementia.295,296,297 Scott et al have shown that, in elderly patients, levels of folate correlate positively with the volume of the hippocampus and amygdala, and inversely with white matter hyperintensities, a marker of neuropathology observable upon MRI brain imaging.298
The brain may be the first organ affected by insufficient intakes of various other B-vitamins as well, including pantothenic acid, riboflavin, and nicotinamide, since these nutrients are important intermediaries in the mitochondrial oxidative phosphorylation (OXPHOS) process, a series of reactions by which chemical energy in the form of adenosine triphosphate (ATP) is produced. The brain produces more energy per unit mass than any other organ in the body, thus reflecting the sheer number of OXPHOS reactions taking place therein.299,300,301
A critical component of the OXPHOS reaction pathway, CoQ10 serves to shuttle electrons between two “stations” along the mitochondrial inner membrane on the pathway to ATP formation. Without adequate CoQ10 supply, electron transport may slow, resulting in fewer ATP molecules being produced, and ultimately less available cellular energy.
CoQ10 supplementation has been shown to improve outcomes in several neurodegenerative disorders involving loss of mitochondrial function, such as Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.302,303 Some animal data provides evidence for CoQ10’s potential for preserving cognitive function in conditions such as experimental Alzheimer’s disease.304
Inhibition of HMG-CoA by the widely-prescribed cholesterol lowing statin drugs is known to deplete levels of CoQ10 in the body. Indeed, studies have shown that co-administration of CoQ10 with statins may ameliorate some of the side effects of the drugs, and individuals with memory complaints who are also taking statin drugs may benefit from supplementation.305,306,307
The amino acids lysine and methionine are biochemically conjoined in vivo to form the compound carnitine. Carnitine is essential for ensuring that fatty acids are transported into the mitochondrial matrix where they fuel aspects of OXPHOS, but under certain conditions, including age-related cognitive decline, endogenous synthesis may be insufficient to support optimal fatty acid transport. Subsequent to delineation of the role of carnitine in energy production, many researchers began to study the effects of supplementation with carnitine, and its more brain-permeable derivative acetyl-L-carnitine, upon various energy-demanding systems and reactions in the body.308
Supplementation with carnitine and acetyl-L-carnitine has been well-documented to ameliorate consequences of disease states with widespread implications for health, including type 2 diabetes and stroke.309,310 However, more impressive is the efficacy of acetyl-L-carnitine in supporting brain health and cognition during normal age related cognitive decline and Alzheimer’s disease. Acetyl-L-carnitine optimizes cognition by acting upon multiple facets of neuronal function, including enhancing efficiency of cholinergic neurotransmission,311 stabilization of neuronal mitochondrial membranes,312 increasing neural antioxidant defenses,313 and enhancing neuron growth through sensitization to neurotrophic factors.314,315
A meta-analysis (comprehensive systematic review) of randomized, controlled human clinical trials involving data from 21 studies and data for over 1,200 subjects with mild cognitive impairment or mild to moderate Alzheimer’s disease provides unequivocal evidence that supplementation with acetyl-L-carnitine ameliorates cognitive deficits observed during aging and during pathological brain deterioration.316 The reviewers found that daily doses of acetyl-L-carnitine ranging from 1.5 – 3.0 grams consistently provided a statistically significant benefit over placebo for preserving cognition as assessed by multiple standardized tests. Moreover, there was a clear trend for a cumulative effect of acetyl-L-carnitine supplementation over time, suggesting that long-term use of acetyl-L-carnitine may provide the greatest benefit.
Like the omega-3’s EPA and DHA, phosphatidylserine is an especially important component of cellular membranes. In the brain phosphatidylserine conjugates with DHA and helps maintain the proper electrical gradient along neuronal membranes, thus facilitating proper neural communication.317 Human clinical trials have found that orally administered phosphatidylserine in doses ranging from 200 mg to 600 mg daily improves cognitive function in aging subjects with cognitive impairment.318,319,320
The leaves of the Ginkgo biloba tree have been highly regarded throughout human history and used as a food additive and as a traditional medicine. Though widely regarded a nootropic, or cognitive enhancer, human clinical data as a whole suggests that supplementation with Ginkgo biloba extract alone, not in combination with other cognitive support ingredients, is minimally effective for improving cognitive function in those with Alzheimer’s disease or cognitive impairment.321 Nonetheless, because studies have shown that supplementation with ginkgo improves cerebral blood flow,322 and other cerebrovascular-related aspects of cognition,323 its use in combination with other brain-supporting nutrients may provide synergistic benefits for cognition. Indeed, results in both animals and humans suggest that, when ginkgo is combined with nutrients such as phosphatidylerine, B-vitamins, or vitamin E, the combination of ingredients confer cognitive benefits.324,325 In fact, in one study comparing the effects of supplementation with Ginkgo biloba extract alone, to Ginkgo biloba extract together with phosphatidylserine, the combination of the two ingredients resulted in improvements in at least two aspects of memory performance, while Ginkgo alone did not. 326
In India, where the Bacopa monnieri herb grows, the leaves are held in high regard, and have long been believed in Ayurvedic medical tradition to promote cognitive health. More recently, modern scientific inquiry into the origins of these Ayurvedic tenets has revealed that the herb supports brain function through various mechanisms.
Bacopa is rich in free radical scavenging compounds including polyphenols and sulfur-based molecules, and so may ameliorate the oxidative stress generated by the brains’ intense metabolic rate.327 It also contains various phytochemicals with known anti-inflammatory properties, such as luteolin and apigenin.328,329 Several human clinical trials have revealed cognitive-enhancing, and memory improving effects of supplementation with Bacopa extract.
In one double-blind, placebo-controlled trial, daily doses of 300 mg of Bacopa extract significantly improved visual information processing speed, memory consolidation, and lessened anxiety in healthy individuals after 12-weeks of supplementation.330 Another double-blind, placebo-controlled study of the same duration, using the same dose of Bacopa extract, found that the benefits extend to elderly subjects as well. In this study, the group receiving Bacopa fared better on an auditory verbal learning test, and scored lower on anxiety and depression scales than those taking placebo.331 Additional promising results were achieved in a similar study in which healthy adults received either 300mg of Bacopa extract daily, or a placebo, for 90-days. Improvements in working memory were noted in the Bacopa group, but not in the placebo group.332
A compound derived from the plant Huperzia serrata, commonly known as clubmoss or firmoss, huperzine A is a well-established inhibitor of the acetylcholinesterase enzyme, a mechanism it shares with many commonly prescribed pharmaceutical treatments for Alzheimer’s disease.333,334 Inhibiton of acetylcholinesterase preserves levels of the neurotransmitter acetylcholine, which is critical for cognition and memory.
Huperzine A has been shown to enhance memory in healthy young humans,335 and in a recent comprehensive literature review, it was found that high doses of huperzine A significantly improved scores on standardized cognitive tests achieved by patients with Alzheimer’s disease in a time-dependent manner.336
Glyceryl Phosphoryl Choline
Glyceryl phosphoryl choline (GPC) is a form of choline that is naturally present in all the body’s cells. Among aging adults, the rationale for GPC therapy goes back to the hypothesis, developed more than 30 years ago, that declining levels of acetylcholine—and a concurrent decrease in the number of neurons that are its intended target—are responsible for a range of cognitive deficits.337 Acetylcholine is an essential neurotransmitter involved in muscle control, sleep, and cognition. Research has shown that GPC is a precursor of acetylcholine that is safe and well tolerated.338 A review of 13 published studies, involving more than 4000 participants, found that patients taking GPC exhibited neurological improvement and relief of clinical symptoms of chronic cerebral deterioration that was clearly superior to placebo and “superior or equivalent” to that obtained with prescription drugs. The same authors found that GPC was superior to choline and lecithin and that it deserved wider study as a therapy for stroke patients seeking to regain full cognitive function.339
A semisynthetic derivative of the lesser periwinkle plant (Vinca minor), vinpocetine has been shown to exert a variety of biological effects that may benefit brain health. It is known to regulate the action of sodium in neurons, lessening the damaging effects of hypoxia as seen in stroke, as well as mitigating oxidative stress.340 Vinpocetine also blunts the activity of an enzyme called phosphodiesterase type 1, an effect which may increase neuronal energy by up-regulating the energy “throttle” cyclic AMP.341 Also, vinpocetine itself has demonstrated the ability to neutralize particularly damaging hydroxyl radicals.342 Moreover, vinpocetine supports healthy blood flow by enhancing vasodilation and blunting platelet aggregation, effects which may enhance cerebral circulation.343,344 Indeed, human clinical trials show that large doses of IV vinpocetine, followed by three months of oral supplementation with 30 mg vinpocetine, eases blood flow in patients with chronic cardiovascular disease.345
Even the healthiest diets may not provide the optimal levels of micronutrients, vitamins, and minerals needed to support healthy brain function. A comprehensive multi-vitamin supplement may help to fill these nutritional gaps and ameliorate some consequences of insufficient dietary nutrition. In a double-blind, controlled clinical trial involving over 200 healthy middle-aged individuals subjects were given either a multi-vitamin or placebo for more than two months, and both groups were then assessed for cognitive function. It was shown that those taking the multi-vitamin displayed less fatigue during extended cognitive challenges, and were also more accurate. Also, those taking multi-vitamins were able to more quickly complete mathematical processing tests than subjects receiving placebo.346
Age-related cognitive decline is associated with reduced synaptic plasticity in the brain. A novel form of magnesium, magnesium-L-threonate, has been shown to enhance signaling through pathways that promote synaptic plasticity.347 Also, Alzheimer’s disease is associated with magnesium deficit and accumulation of amyloid-beta plaques in the brain.348 Magnesium-L-threonate has been shown to boost brain magnesium levels and enhance the clearance of amyloid-beta in preclinical and laboratory research.349,350 In a mouse model of Alzheimer’s disease, treatment with magnesium-L-threonate reduced amyloid-beta accumulation, prevented synapse loss, and reduced memory decline. Magnesium-L-threonate conferred benefit even when given to mice with advanced-stage Alzheimer’s-like disease.351 This novel magnesium compound was also shown to combat inflammatory processes in the brain by preventing upregulation of the inflammatory mediator TNF-α.350
Pyrroloquinoline Quinone (PQQ)
Pyrroloquinoline quinone, or PQQ, is a highly bioactive compound present in a vast range of cell types, and research suggests boosting PQQ levels may improve mitochondrial function, inhibit oxidative stress, and support neurological health.366-371
Research indicates PQQ is a neuro-protectant that can promote nerve repair. A number of laboratory and animal studies indicated PQQ can protect nerve cells from toxic and inflammatory damage by reducing oxidative stress and protecting mitochondria.372-375 In a study in rats exposed to high levels of oxidative stress, PQQ supplementation protected against memory loss.376 Several studies showed PQQ may prevent the accumulation of damaging amyloid proteins, which might protect against conditions such as Alzheimer’s disease and Parkinson’s disease.377-380 PQQ has also been found to stimulate the production of a protein called nerve growth factor and promote the regeneration of nerves in animals.381-384
In two clinical trials, PQQ increased regional brain blood flow and oxygen use, resulting in improved cognitive function. In 41 healthy elderly subjects, 20 mg PQQ daily for 12 weeks resulted in higher cognitive test scores compared with placebo. In addition, scores on visual/spatial cognitive tests improved significantly in those receiving PQQ that had the lowest scores at the beginning of the trial. Near-infrared spectrometry results also suggested PQQ supplementation increased cerebral blood flow.370 Another study using near-infrared spectrometry confirmed taking 20 mg PQQ daily for 12 weeks led to increased regional brain blood flow and oxygen utilization in healthy subjects.385
Nicotinamide riboside is a source of vitamin B3 that the body uses as a precursor for nicotinamide adenine dinucleotide (NAD), a molecule involved in a range of critical biological processes.386 NAD+, a biologically active form of NAD, is necessary for the activation of sirtuins, proteins that modulate cellular metabolism and DNA transcription.386-388 NAD+-dependent sirtuins appear to be involved in essential cellular activities including energy metabolism, DNA damage response, stress resistance, proliferation and differentiation, survival, and aging,389 and in animal research have been shown to be involved in brain connectivity and memory formation.390 NAD+ levels decrease with age, which may cause dysfunction in cell nuclei and mitochondria, ultimately contributing to age-related disorders including cognitive decline.388,389 Restoration of NAD+ with supplemental nicotinamide riboside has been shown to reverse age-related cellular dysfunction, which contributes to many neurodegenerative diseases, while models of neurodegenerative disease indicate nicotinamide riboside may be neuroprotective.386,388,391-393
In a six-month controlled clinical trial in 26 individuals with probable Alzheimer’s disease, those who received the NADH form of nicotinamide adenine dinucleotide had no progression in cognitive decline and significantly better scores on a dementia rating scale compared with the placebo group.394 In rodents, NADH administration in older animals resulted in improved performance on cognitive tests.395 In a mouse model of Alzheimer’s disease, three months of nicotinamide riboside supplementation led to increased brain levels of NAD+, prevented cognitive decline, and reduced production of neuron damaging amyloid-beta proteins.396
Lithium is a mineral used as a mood stabilizer, particularly in the treatment of bipolar disorder and major depression.397 Animal and laboratory research indicate lithium may have neuroprotective effects and may preserve cognitive function in models of cognitive decline and Alzheimer’s disease.398-401 In humans, lithium appears to increase brain mitochondrial functioning, reduce brain oxidative stress and markers of inflammation, promote production of BDNF, and benefit areas of the brain involved in memory and cognitive activities.397,402
Lithium supplementation may enhance cognitive function.403,404 Early evidence from animal and human studies suggest lithium may be protect against cognitive losses associated with ischemic stroke, cancer treatment, and neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.405-408 In a pilot study, patients with Alzheimer’s disease treated with 300 micrograms lithium per day (at least 3000 times lower than typical doses used to treat bipolar disorder) for 15 months experienced no changes in cognitive performance, while their untreated counterparts experienced significant cognitive losses.409 In a pilot trial in 45 subjects with amnestic mild cognitive impairment (a condition that frequently progresses to Alzheimer’s disease), those who received lithium performed modestly better on some cognitive function tests over a 12-month period compared with placebo, although this difference was small and not statistically significant.410
Findings from animal studies suggest the positive effects of lithium on memory and cognitive function may be enhanced by the simultaneous use of zinc or pyrroloqinoline quinone.411,412
The neuroprotective effect of lithium appears to be related to its ability to inhibit an enzyme known as glycogen synthase kinase 3 (GSK-3). This enzyme catalyzes reactions that join phosphates to proteins called tau proteins. Overly phosphorylated tau proteins aggregate and form the basis of the neurofibrillary tangles correlated with cognitive decline in Alzheimer’s disease.413-415 By inhibiting GSK-3, lithium helps regulate tau protein phosphorylation and prevent neurofibrillary tangle formation.413 GSK-3 inhibition has also been associated with reduced amyloid production.416,417 Furthermore, animal and laboratory research show lithium treatment may increase brain levels of a neuroprotective protein called beta-cell lymphoma 2 (Bcl-2).418
Because doses of lithium used to treat bipolar disorder (typically 900–1800 mg per day) are well known to cause a number of side effects,419 including kidney toxicity and brain cerebellar toxicity and atrophy (shrinking),420,421 researchers have been monitoring the effects of long-term use of lower doses. A preliminary, randomized, controlled trial in 61 older subjects with mild cognitive decline receiving low-dose lithium found no significant evidence of kidney damage after four years of treatment; however, lithium-treated subjects had higher incidence of weight gain, decreased thyroid function, new-onset diabetes, and abnormal heart rhythms. The lithium doses used in this study were ≥ 150 mg per day, and individualized to maintain serum levels between 0.25 and 0.50 mmol/L.422 While lithium appears to hold potential for people with cognitive decline, these findings point to more research needed to determine ideal dosing and long-term safety.
Colostrinin (Proline-rich peptide complex)
Colostrum—the first breast milk secreted after childbirth—is known for its high levels of antibodies and other factors with immune-activating effects.423 Findings from preclinical and clinical studies suggest colostrinin, a proline-rich polypeptide complex in colostrum, may help prevent the progression of cognitive decline, particularly in people with Alzheimer’s disease.424,425 A number of studies have found a range of possible mechanisms for colostrinin’s beneficial effects, including modulating immune activity; preventing oxidative stress, including oxidative damage to DNA; anti-inflammatory activity; inhibiting overproduction of nitric oxide; and decreasing age-related mitochondrial dysfunction.426-431
A double-blind placebo-controlled trial compared colostrinin to placebo in 105 subjects with mild-to-moderate Alzheimer’s disease. The colostrinin group received 100 micrograms 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-week treatment cycle. Colostrinin treatment had a stabilizing effect on cognitive function and ability to perform activities of daily living. Participants with mild cognitive impairment responded better to treatment than those with more advanced decline.432 Another trial used the same dosing schedule for 16 to 28 months in 33 Alzheimer’s patients and found it resulted in stabilization or improvement in health status.433 An earlier double-blind placebo-controlled trial was conducted in 46 patients with Alzheimer’s disease and mild-to-moderate dementia. Subjects received either 100 micrograms colostrinin, 100 micrograms selenium, or placebo every other day in three-week treatment cycles, followed by two weeks of no treatment. Eight of 15 colostrinin patients improved, while seven of them experienced stabilization of their condition; in contrast, none of the patients in the selenium or placebo groups improved.434 Studies reported colostrinin was well tolerated with mild side effects that passed quickly.433,434
Studies in which cultured nerve cells were treated with colostrinin or a nanopeptide fragment of colostrinin have demonstrated their potential to disrupt amyloid beta fibrils and prevent further accumulation and neurotoxic effects of amyloid beta.435-438
Cocoa has been consumed by humans for thousands of years,439 and its medicinal use has been documented for hundreds of years.440 Modern research shows cocoa and chocolate have powerful brain-boosting benefits.
A study in 309 subjects age 65 assessed the association of chocolate intake and cognitive decline, with a median follow-up of four years. In individuals whose caffeine intake was less than 75 mg per day (roughly the amount in a six ounce cup of coffee or two cups of tea),441 those who consumed chocolate had a 50% reduced risk of cognitive decline.442 Another study in 968 adults found higher chocolate consumption was correlated with better performance on cognitive function tests.443
A double-blind clinical trial has shown that cocoa consumption can support healthy blood flow in the brain and support cognition. Sixty adults with an average age of 73 and high blood pressure and/or well-controlled type II diabetes consumed two cups of a cocoa drink daily for 30 days. All subjects had their neurovascular coupling and cognitive function measured at baseline and on days 1 and 30 after beginning the cocoa consumption. After 24 hours, subjects with impaired neurovascular coupling at baseline had a 10.6% improvement, and by day 30, these subjects’ performance on a test requiring attention significantly improved. The baseline time to complete this test was 167 seconds versus 116 seconds at day 30.444
Spearmint (Mentha spicata) is an aromatic herb used traditionally to enhance memory and cognition.445 It is rich in water-soluble polyphenols, many of which have anti-inflammatory and free radical-reducing properties. Rosmarinic acid and its derivatives generally appear to make up the greatest proportion of spearmint’s polyphenols.446 Spearmint and rosmarinic acid have been found to inhibit enzymes that break down neurochemicals involved in learning, memory, and mood.445,447-448
In one trial, 11 subjects with self-reported mild memory impairment were given 900 mg of high-rosmarinic acid spearmint extract per day for 30 days. At the end of the treatment period, performance on tests of reasoning, attention, and concentration improved significantly. Even short-term administration resulted in improvements in attention and concentration within 2–4 hours.449
In animal studies, rosmarinic acid demonstrated neuroprotective properties450,451 and improved cognitive function.447,452 In one such study, mice with an experimental form of age-related cognitive impairment exhibited better memory and learning, and had less evidence of brain tissue oxidation, after treatment with a spearmint extract containing 5% rosmarinic acid.453
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