Age Related Cognitive Decline

Age Related Cognitive Decline

1 Overview

Summary and Quick Facts

  • Mild cognitive impairment is the condition characterized by cognitive changes that are more than expected for age, but are not debilitating. It is estimated that 10 to 20 percent of adults aged 65 years and older have mild cognitive impairment.
  • This protocol will review many underlying factors that contribute to cognitive decline and describe several innovative medical strategies, lifestyle and dietary habits and integrative interventions that can support healthy cognitive function and brain health throughout life.
  • Proactive lifestyle changes, cognitive training and nutritional interventions such as phosphatidylserine and glyceryl phosphoryl choline have been shown to decrease the rate of intellectual decay and potentially reverse age-related cognitive decline.

All aging humans will develop some degree of decline in cognitive capacity, usually including the following symptoms:

  • forgetfulness
  • decreased ability to maintain focus
  • decreased problem solving capacity

If left unchecked, symptoms oftentimes progress into more serious conditions, such as dementia and depression, or even Alzheimer’s disease.

Fortunately, proactive lifestyle changes, cognitive training, and nutritional interventions such as phosphatidylserine and glyceryl phosphoryl choline have been shown to decrease the rate of intellectual decay and potentially reverse age-related cognitive decline.

Causes of Age-Related Cognitive Decline

Many factors contribute to age-related cognitive decline:

  • Oxidative stress and free radical damage
  • Chronic low-level inflammation
  • Declining hormone levels like estrogen, testosterone, DHEA, pregnenolone
  • Inner arterial lining (endothelium) dysfunction
  • Insulin resistance
  • Excess body weight
  • Suboptimal nutrition
  • Loneliness, lack of social network, and high stress

Dietary and Lifestyle Changes

Several dietary and lifestyle changes can help reduce age-related cognitive decline:

  • Switch from a western diet high in simple sugars and saturated fats to a Mediterranean diet high in mono- and polyunsaturated omega-3 fats, fiber, and polyphenols
  • Caloric restriction may improve learning and memory
  • Cognitive stimulation and training, including playing chess and speaking more than one language, can enhance cognitive reserve and convey protection against loss of brain function
  • Exercise is known to increase levels of brain-derived neurotrophic factor, which can lead to enhanced cognitive function
  • Moderate alcohol consumption (up to 2 drinks/day) and caffeinated coffee consumption (~3 cups/day) may convey protection against cognitive decline

Integrative Interventions

  • Fish Oil: 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.
  • Phosphatidylserine: Human clinical trials have found that supplementing with phosphatidylserine improves cognitive function in aging subjects with cognitive impairment.
  • Glyceryl Phosphoryl Choline (GPC): Patients taking GPC showed neurological improvement and relief of clinical symptoms of chronic cerebral deterioration that was superior or equivalent to that obtained with prescription drugs.
  • Acetyl-L-carnitine: A meta-analysis of data from over 21 studies shows that supplementation with acetyl-L-carnitine improves cognitive deficits observed during aging and pathological brain deterioration.
  • Huperzine A: Patients with Alzheimer’s disease improved their scores on standard cognitive tests after supplementing with huperzine A.
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2 Introduction

Cognitive function appears to peak around age 20 and diminish steadily over the remaining years of life.1,2 With life expectancies increasing dramatically in the last century, cognitive decline and dementia have become major contributors to disability and mortality.3,4

Aging is associated with gradual changes in the brain that slow and reduce its function. As a result of these changes, it is common for elderly people, even those without neurological disease, to find it takes longer to perform mental tasks and to experience diminished memory, attention, and abilities to learn, reason, and solve problems.2 Although some cognitive decline occurs during normal aging, its rate of progression is affected by lifestyle, environmental, and genetic factors,5 some of which may be modifiable.1,6

Aging is a complex process, and age-related conditions like cognitive decline are multifactorial. Some factors that likely contribute to age-related cognitive decline are:

  • stem cell senescence,
  • brain oxidative stress and mitochondrial dysfunction,
  • neuroinflammation (inflammation in the brain),
  • circadian rhythm and metabolic disturbances,
  • vascular dysfunction,
  • abnormal protein accumulation,
  • disordered homocysteine metabolism,
  • changing hormone levels, and
  • epigenetic factors—changes in the way genes are expressed.

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

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

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

3 Background

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

The Aging Brain

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

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

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

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

Age-related cognitive decline is the term used to describe the natural diminishment in ability to learn, remember, and process information. Mild cognitive impairment is the condition characterized by cognitive changes that are more than expected for age, but are not debilitating. It is estimated that 10–20% of adults aged 65 years and older have mild cognitive impairment.16,17

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

Distinguishing between normal age-related cognitive change and mild cognitive impairment is challenging, but a comprehensive assessment that includes a history of cognitive changes, physical exam, neurological exam, and cognitive function testing is the basis of accurate diagnosis.18

Table 1: Domains of cognitive decline and functional signs of impairment17

Cognitive Domain

Signs of Impairment

Executive function

Difficulties with:

- Planning

- Organizing

- Multitasking

- Following directions

- Keeping up with shifting conversations

Attention

- Normal tasks take longer or need to be simplified

- Difficulty focusing in conditions with multiple stimuli

- Distractibility

- Difficulty holding information in mind for tasks such as mental calculations or dialing a phone number

Visuospatial skills

- Getting lost in familiar places

- Difficulty using familiar tools or appliances

- Increasing need for notes and maps

Language

- Difficulty finding words

- Using words or phrases wrong

- Difficulty with written and verbal language comprehension

- More frequent grammatical errors

Memory and learning

- Difficulty remembering recent events

- Repeating oneself

- Misplacing items

- Losing track of actions that have already been done

- Increasing need for lists and reminders

Social cognition

- Disinhibition or apathy

- Loss of empathy

- Inappropriate behavior

- Loss of judgement

Risk Factors Associated with Cognitive Decline

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

  • Sedentary lifestyle21,22
  • Low educational attainment21,22
  • Smoking21,22
  • Obesity21,22
  • Insulin resistance and type 2 diabetes21,22
  • Hypertension21,22
  • High cholesterol levels21,22
  • Chronic kidney disease21
  • Atrial fibrillation (a type of arrhythmia)21
  • Cardiovascular disease24
  • Depression21
  • Sleep disorders25
  • Sleep apnea26
  • High homocysteine levels27
  • Heavy metal toxicity28

Sleep Medications and Cognitive Dysfunction

Although sleep disorders are a common contributor to both acute and chronic cognitive problems, some medications used to treat sleep disorders have been linked in some studies to increased risk of dementia. This includes prescription sleep medications, such as benzodiazepines, as well as some over-the-counter sleep aids.29-31

Benzodiazepines are a class of sedative medications that alter neurotransmission and are indicated for short-term treatment of anxiety and insomnia; nevertheless, chronic use of benzodiazepines is common.30 Long-acting benzodiazepines, like clonazepam (Klonopin) and diazepam (Valium), are more likely to contribute to dementia risk than those with a shorter action, such as triazolam (Halcion) and midazolam (Versed).30 A newer class of sedatives known as Z-drugs is approved for long-term treatment of insomnia, but some evidence suggests their use may also contribute to dementia risk. Examples of Z-drugs are zolpidem (Ambien), zopiclone (Imovane), and eszopiclone (Lunesta).29

4 Mechanisms Involved in Age-Related Cognitive Decline

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

Stem Cell Senescence

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

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

Circadian Rhythm Disturbance

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

Cerebrovascular Dysfunction

The term “cerebrovascular” refers to the blood vessels supplying the brain. Cerebrovascular dysfunction, driven by aging and atherosclerosis of the blood vessels in the brain, results in decreased cerebral blood flow. With age, cerebral blood vessels become stiffer and less responsive to changing blood pressures and oxygen and nutrient demands. In addition, capillary beds in the brain become more susceptible to injury and inflammation, increasing risk of developing small blood clots and microbleeds that can destroy neurons and negatively impact cognitive function.43-46

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

Neuroinflammation

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

Mitochondrial Dysfunction and Oxidative Stress

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

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

Metabolic Disturbance

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

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

Concussion and Cognitive Decline

Concussion, also known as mild traumatic brain injury, is now widely recognized as a potential contributor to long-term cognitive dysfunction. Until recently, the effects of concussion were believed to resolve spontaneously in a matter of months in the majority of people. We now know that as many as half of all individuals with a single concussion experience chronic cognitive impairment.58 Repeated head traumas, which are common in athletes, may further increase long-term risks.59,60

Several mechanisms appear to be at play in the cognitive sequelae of concussion. Laboratory models of head injury suggest mild traumatic brain injury, particularly when repeated, may trigger a cascade of overlapping processes in the brain, such as60,61:

  • altered glucose metabolism and energy production by neuronal mitochondria
  • increased oxidative stress and oxidative damage to critical lipid brain structures
  • decreased cerebral blood flow
  • heightened activity of microglial cells, exacerbating neuroinflammation
  • disrupted blood‒brain barrier function
  • altered neurotransmission
  • decreased removal of amyloid and tau proteins

Furthermore, concussion may trigger neuronal death and initiate long-term degenerative processes.61 Studies using imaging techniques have revealed structural changes in brain tissue following head injury that are associated with decreases in attention, memory, and executive function.62 The effects of concussion appear to interact with age-related processes to accelerate loss of cognitive reserve and increase risk of cognitive impairment and dementia years later.63

Clinicians and researchers are still exploring strategies for minimizing the short- and long-term problems associated with concussion. In the meantime, protecting the head during high-risk activities is imperative. If you do experience a head injury, following recommendations for protecting the aging brain may be beneficial, whatever your age.

Abnormal Protein Accumulation

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

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

Epigenetics

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

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

Disrupted Homocysteine Metabolism

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

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

Fibrinogen and Cognitive Decline

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

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

Hormone Imbalance

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

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

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

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

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

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

Postoperative Cognitive Dysfunction

Postoperative cognitive dysfunction refers to a persistent cognitive impairment following surgery, frequently affecting orientation, attention, perception, consciousness, and judgement.97 Many surgery patients experience acute cognitive symptoms shortly after surgery, known as postoperative delirium, which lasts up to about four days. Cognitive changes such as confusion, reduced attention, and decreased awareness of surroundings are hallmarks of postoperative delirium. In about 10% of surgical patients, a more persistent cognitive impairment occurs. Older patients and those with pre-existing cognitive impairment are at higher risk of chronic postoperative cognitive effects.98 Cerebrovascular problems have also been linked to increased risk of postoperative cognitive dysfunction.99 Postoperative cognitive decline lengthens recovery time and hospital stays and is associated with poorer surgical outcomes.97

Although its cause is not entirely known, evidence suggests surgical trauma initiates an inflammatory response that, through communication between systemic and brain immune cells, triggers neuroinflammation. Both systemic and brain inflammation can also induce blood‒brain barrier dysfunction, giving rise to more inflammatory activity in brain tissue.100,101 Older age increases the risk of postoperative cognitive dysfunction, possibly due to the immune dysregulation that characterizes the aging immune system.102 Inflammation also increases oxidative stress and depletes the body’s antioxidants, which may further contribute to neuronal damage and dysfunction.103 Anesthesia’s potential effects on cognitive function add to the complexity, but observational studies have found that risk of postoperative cognitive dysfunction may not be related to the type of anesthesia used or even the type of surgery performed.101,103

Surgical recovery may be supported through a set of evidence-based pre-, peri-, and post-operative care protocols aimed at reducing stress, maintaining organ function, and accelerating restoration of gut function. They include measures such as counseling, physical activity, mental training, and nutritional interventions prior to surgery; ensuring adequate nutrition and avoiding unnecessarily long fasting periods immediately before procedures; using the least invasive surgical procedures and anesthesia techniques; judicious use of pain and other medications postoperatively; and resumption of healthy diet, promotion of daily rhythms and sleep, and early mobilization after surgery. These measures have been shown to enhance postsurgical recovery in general and may be useful in reducing the risk of postoperative cognitive decline.97,104

5 Nootropic Drugs and Novel Approaches to Cognitive Decline

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

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

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

Several other medications with potential brain-protective effects are:

  • Piracetam (Nootropil) and levetiracetam (Keppra) are anti-seizure medications sometimes used as cognitive enhancers. These and several related drugs (the “racetams”) are often colloquially referred to as “nootropics.” Preclinical evidence suggests these medications may reduce neuroinflammation, improve mitochondrial function, and prevent β-amyloid-induced neuronal dysfunction.117-119 In early research, levetiracetam was found to improve cognitive performance on a memory test.120 Findings from a clinical trial in cognitive impairment and dementia patients suggest piracetam may be most effective in those with depressive symptoms.121 Whether these medications hold benefits for patients with age-related cognitive decline and mild cognitive impairment has not yet been established. Also, the regulatory status of piracetam and related compounds is vague, and legal status varies between countries.
  • Zileuton (Zyflo) is an inhibitor of the pro-inflammatory enzyme 5-lipoxygenase. While its main use is as an anti-asthma medication, zileuton has demonstrated some intriguing effects on brain function in preclinical trials. In animal research, zileuton has been found to reduce brain levels of β-amyloid and tau, as well as amyloid- and tau-related neuroinflammation, neuronal dysfunction, and cognitive impairment.122-125 Other animal research suggests zileuton may reduce brain damage and cognitive losses after stroke.126-128 The possible usefulness of zileuton in age-related cognitive decline, mild cognitive impairment, and dementia awaits future investigation.
  • Hydergine (co-dergocrine mesylate), a mixture of ergot alkaloids, has been found to improve cognitive function and mood in preliminary trials in elderly subjects with age-related cognitive dysfunction.129,130 Its mechanism of action is not completely understood; however, it appears to modulate neurotransmitter activity, improve cerebral metabolism, and increase antioxidant enzyme activity in the brain.131,132 Despite interesting findings, there have been no clinical trials investigating hydergine’s usefulness in age-related cognitive decline and mild cognitive impairment for decades.
  • Selegiline or deprenyl (Eldepryl) is a monoamine oxidase-B inhibitor that blocks the enzymatic breakdown of certain neurotransmitters, such as dopamine and serotonin. It is used to treat Parkinson disease, Alzheimer disease, and major depressive disorder, and is thought to have anti-aging effects.133 Selegiline was found to improve cognitive performance in a six-month preliminary trial in human subjects with mild-to-moderate brain atrophy.134 Studies in animals suggest it can reduce oxidative stress, protect against brain damage due to loss of blood flow, and preserve neurotransmission and memory.135-138 More clinical trials are needed to ascertain the potential benefits of this medication in age-related cognitive decline.
  • Centrophenoxine or meclofenoxate (Lucidril) enhances activation of cholinergic pathways in the central nervous system. An early trial in elderly subjects found centrophenoxine improved formation of new memory and increased subjective reports of mental alertness.139 Animal research has found that this medication may protect against cognitive losses due to aluminum toxicity,140 drug toxicity,141 and lack of blood flow.142

6 Dietary and Lifestyle Consideration for Brain Health

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

Physical Activity

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

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

A large body of evidence indicates that any type and amount of physical activity is better than none when it comes to cognitive health. It is clear that both aerobic exercise and strength training can prevent or delay cognitive decline in older adults, regardless of their current cognitive status.145 Even seated exercises have cognitive benefits for older patients who are unable to exercise upright.146

Mental Activity

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

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

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

Stress Reduction

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

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

Social Engagement

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

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

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

Sleep

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

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

According to large meta-analyses of research into this relationship, the optimum amount of sleep for healthy cognitive function appears to be 7–8 hours per night, with both shorter and longer sleep durations associated with increasing risks of cognitive decline, mild cognitive impairment, and dementia.184,185

Sufficient daily activity and a nighttime environment that promotes sleep may help older people struggling with sleep disorders. Strategies that have demonstrated some effectiveness include181,186,187:

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

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

Obstructive Sleep Apnea and Cognitive Dysfunction

Obstructive sleep apnea is a common form of sleep-disordered breathing characterized by periodic episodes of complete or partial airway closure, resulting in apnea (lack of breathing) or hypopnea (insufficient breathing), during sleep. Falling blood levels of oxygen and rising levels of carbon dioxide as a result of apnea and hypopnea cause brain arousal that triggers the resumption of sufficient breathing.188 Frequent cycling between apnea and arousal causes sleep fragmentation that, when chronic, can lead to disrupted circadian signaling, dysregulation of the stress response, systemic inflammation, and increased oxidative stress.189,190 Obstructive sleep apnea can be a major contributing factor in metabolic and cardiovascular diseases, as well as cognitive dysfunction.190,191

The relationship between obstructive sleep apnea and cognitive decline, mild cognitive impairment, and dementia has been observed in numerous studies.188,192 According to a large meta-analysis that included 14 studies with over 4 million participants, sleep-disordered breathing is associated with a 26% increased likelihood of developing cognitive impairment.26 A growing body of evidence suggests treatment of sleep apnea with continuous positive airway pressure (CPAP) can reduce sleep apnea-related cognitive decline.193-195

More information is available in Life Extension’s Sleep Apnea protocol.

Diet

An eating pattern based on the traditional Mediterranean diet has been shown to have anti-aging effects on brain, cardiovascular, and metabolic functions, and on overall longevity.143,196-198 Findings from a variety of studies suggest eating a Mediterranean-style diet can slow cognitive decline and may reduce risk of dementia.199

Mediterranean diet. With its emphasis on fruits, vegetables, unrefined whole grains, legumes, and extra virgin olive oil, as well as moderate amounts of seafood, fermented dairy products, and red wine with meals,200 the traditional Mediterranean diet provides ample amounts of critical nutrients such as mono- and polyunsaturated fatty acids, antioxidants, vitamins, minerals, and phytonutrients. It can be used as a template that can be adapted to favor local and seasonal availability of specific foods.143,198

A study including 832 participants examined every two to three years for up to 18 years found that those whose diets most closely reflected a Mediterranean diet experienced significantly less cognitive decline than those whose diets least reflected a Mediterranean diet.201 A study based on data collected over 16 years from 27,842 men participating in the Health Professionals’ Follow-up Study found that those whose diets were most Mediterranean-like were 36% less likely to report poor subjective cognitive function than those whose diets were least Mediterranean-like.202 Examining the brains of cognitively normal older-age subjects has revealed that adherence to a Mediterranean-like dietary pattern is associated with reduced β-amyloid accumulation. The components of the diet most closely linked to this effect were high fruit and vegetable consumption and moderate wine consumption.203,204

Table 2. Strategies for Transitioning from a Western-style Diet to a Mediterranean-style Diet200

Staples of a Mediterranean Diet

Staples of a Western Diet

Incorporating Mediterranean Eating Patterns

Olive oil

Solid fats;

Corn, soybean, canola and sunflower oils

Use extra virgin olive oil on vegetables, legumes, salads, stir-fries, and sautés;

Flavor food with herbs, spices, garlic, onion, and lemon

Vegetables

Mainly starchy vegetables

(Low consumption)

Have vegetables with both lunch and dinner;

Use vegetables as a main dish often;

Have some raw, dressed with olive oil and vinegar, every day

Fruits

Fruit products often contain added sugar

(Low consumption)

Eat raw fruits as dessert most days;

Include a variety of seasonally appropriate fruits

Unrefined whole grains

Refined white flour;

Processed cereals with added sugars;

White flour bread, pasta, pastries

Use whole grain bread, pasta, and flour;

Include whole unrefined grains often

Legumes

Canned beans high in added salt and sugar

(Low consumption)

Include a variety of beans, lentils, and peas;

Cook dried beans or choose canned beans without additives

Nuts and olives

Processed snack foods and condiments;

High-fat, high-sugar sauces and dips

Have nuts and olives as snacks;

Eat a handful of raw nuts daily;

Choose a variety of nuts

Moderate seafood intake

Low consumption

White fish (cod, flounder, tilapia) once or more weekly;

Fatty fish (tuna, salmon, sardines) twice or more weekly;

Shellfish (oysters, clams, squid, shrimp) occasionally

Moderate fermented dairy (yogurt and cheese)

High intake of milk, processed cheeses, ice cream

Use unsweetened yogurt and flavor with fruit;

Have small amounts of fresh or cured cheese occasionally;

Avoid ice cream

Limited intake of homemade baked goods

Processed baked goods (high in sugar, processed fats, and additives)

Bake at home;

Use olive oil instead of butter;

Eat baked goods only occasionally

Little meat and limited poultry

High intake of red and processed meats;

Large portions

(Daily consumption)

Choose lean poultry;

Have moderate portions, not daily

Red wine

Beer, liquor, and sugar-sweetened soft drinks

Include moderate amounts (up to 1 glass per day for women and 2 glasses per day for men) of wine, preferably red, always with meals;

Drink water instead of soft drinks

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

Coffee

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

Caloric Restriction

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

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

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

Celiac Disease, Gluten Sensitivity, and Cognitive Decline

Celiac disease is a chronic condition caused by an autoimmune response to gluten, a protein found primarily in wheat. Patients with celiac disease typically have a high degree of systemic and gastrointestinal inflammation, as well as a marked imbalance of gut microorganisms (dysbiosis).223 It is estimated that 10% of celiac disease patients also experience neurological symptoms related to the condition, such as headaches, lack of muscle coordination, numbness or tingling of extremities, depression, and cognitive impairment ranging from mild reversible cognitive symptoms (such as “brain fog”) to permanent neurological damage and dementia.223-225

Non-celiac gluten sensitivity is a gastrointestinal disorder caused by an inflammatory reaction to gluten that does not appear to involve autoantibodies. It can lead to similar consequences as celiac disease, including gut and systemic inflammation and dysbiosis, potentially leading to neuroinflammation and cognitive symptoms.226

In older individuals, neurological manifestations of celiac disease and non-celiac gluten sensitivity are frequently attributed to age-related cognitive decline or misdiagnosed as cognitive impairment or even Alzheimer dementia, yet with accurate diagnosis and implementation of a gluten-free diet, these symptoms often resolve.223,227

7 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

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