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Age Related Cognitive Decline

Age Related Cognitive Decline

All aging humans will develop some degree of decline in cognitive capacity as time progresses. Data indicates that deterioration of the biological framework that underlies the ability to think and reason begins as early as the mid twenties and includes a drop in regional brain volume,1,2,3,4,5 loss of myelin integrity,6,7 cortical thinning,8,9 impaired serotonin, acetylcholine, and dopamine receptor binding and signaling,10,11,12,13 accumulation of neurofibrillary tangles,14 and altered concentrations of various brain metabolites.15 Cumulatively these changes give rise to a variety of symptoms associated with aging, such as forgetfulness, decreased ability to maintain focus, and decreased problem solving capability. If left unchecked, symptoms oftentimes progress into more serious conditions, such as dementia and depression, or even Alzheimer’s disease.

Cognitive decline does not affect all individuals equally; clear associations exist between the rate and severity of cognitive decline and a variety of factors, including oxidative stress and free radical damage,16,17,18 chronic low-level inflammation,19 declining hormone levels,20 endothelial dysfunction,21 excess body weight,22 suboptimal nutrition,23 lifestyle,24 social network,25 other medical conditions,26 and various biomarkers.27 Fortunately, many of these factors are modifiable to a significant extent, and proactive lifestyle changes, cognitive training, and nutritional interventions have been shown to decrease the rate of intellectual decay and potentially reverse age-related cognitive decline.

The Aging Brain

The Aging Brain
Figure 1: Anatomy of a neuron

The aging process profoundly impacts the brain in ways that can be observed on multiple levels, ranging from sub-cellularly to macro-structurally. On a diminutive scale, aging causes deterioration of neuronal and mitochondrial membranes, which leads to the loss of cellular integrity and impaired neuronal function.28,29,30 Steep age-related declines in neurotransmitter synthesis and signaling,31,32,33 coupled with reductions in synaptic density and plasticity (adaptability),34,35 and loss of as much as 50% of the length of myelinated axons36 (see figure 1) make the brain increasingly less efficient as we age.

In a broader sense, the physical structure of the brain as a whole also deteriorates with age. Shrinkage and death of neurons, and reductions in the number of synaptic spines and functional synapses contribute to annual reductions of as much as 0.5% to 1.0% in cortical thickness (the cortex is the outermost layer of the brain) and sub-cortical volume in some regions of the brain.37 Specifically, even in healthy individuals, aging accounts for volume variances of 37% in the thalamus, which is involved in sight, hearing, and the sleep-wake cycle; 36% in the nucleus accumbens, which plays a major role in mood regulation (e.g. pleasure, fear, reward); and 33% in the hippocampus, a critical site for consolidation of short-term to long-term memory.38 Taken together, age related neuroanatomical changes account for an estimated 25% to 100% of the variance in cognitive ability between young and aged individuals.39 In other words, age related cognitive decline occurs in tandem with the physical degradation of brain structure. Thus, conserving cognitive vigilance into late life requires early and aggressive intervention to preserve the brain in its youthful physical and functional state.

Biological Risk Factors Contributing to Cognitive Decline

Various biological systems work in conjunction to maintain optimal brain function and cognitive ability. Perturbations in the harmony of these systems, caused by such age-associated insults as chronic inflammation40 oxidative stress,41 insulin resistance,42 declining hormone levels,43 and endothelial dysfunction,44 result in physical deterioration of the brain and subsequent cognitive decline.

Oxidative Stress

The brain is particularly susceptible to oxidative damage since it consumes roughly 20% of the oxygen used by the entire body, and because it contains high concentrations of phospholipids, which are especially prone to oxidative damage in the context of high metabolic rate.45 As we age, there is a significant and progressive increase in the level of oxidatively damaged DNA and lipids in the brain; this is true even for healthy individuals.46 Over time, this free radical damage leads to the death of neurons.

Numerous studies have implicated oxidative stress in the pathology of mild cognitive impairment and Alzheimer’s disease alike.47,48,49

In a study of 338 individuals, researchers analyzed blood samples from patients with various neurodegenerative diseases and found that the antioxidant capacity of their blood was reduced by as much as 28%, relative to healthy controls. Subjects with a neurodegenerative condition also exhibited significantly increased levels of thiobarbituric acid reactive substances, a marker of free radical damage.50

A separate study, in which researchers examined the plasma of 34 subjects with mild cognitive impairment, 45 with Alzheimer’s disease, and 28 age-matched healthy controls, revealed that patients with mild cognitive impairment or Alzheimer’s disease displayed markedly increased oxidative damage. Subjects with mild cognitive impairment or Alzheimer’s disease exhibited increased protein oxidation (protein carbonyls) and decreased levels of glutathione, a powerful endogenous antioxidant.51

In aged rodents exhibiting signs of cognitive deterioration, increased oxidation of key proteins involved in neuronal metabolism and energy production has been observed.52 Old animals also display dramatically reduced ability to combat oxidative stress, as assessed by a loss of efficiency of thiol reducing systems.53


The inflammatory process in the brain is unique in that the blood-brain barrier (BBB) (tight layer of endothelial cells that separates the brain from regular systemic circulation), during healthy conditions, prevents the infiltration of inflammatory agents and allows only select nutrients and small molecules into the central nervous system (CNS).54 However, chronic systemic inflammation induced by stimuli such as cigarette smoking, obesity, disrupted sleep patterns and poor dietary habits compromises the integrity of the BBB, allowing irritants to enter the brain and stimulate the production of inflammatory cytokines, such as IL-1β, IL-6 and IL-18.55 Inside the CNS, these cytokines impair neurogenesis, the process by which new neurons are generated.56,57,58,59 Aside from inhibiting neurogenesis, some inflammatory cytokines, such as IL-1β, IL-6 and TNF-α damage and destroy existing neurons.60,61

Several studies have linked biomarkers of inflammation with cognitive impairment.

A prospective study of 779 healthy, high-functioning men and women found that subjects in the highest tertile (one-third) for blood levels of IL-6 were significantly more likely to score below the median when assessed for cognitive function at baseline. During follow-up seven years later those same individuals more frequently exhibited declines in cognition compared to their counterparts with lower baseline IL-6 levels.62

In a study of 97 women between 60 and 70 years of age, elevated baseline high sensitivity C-reactive protein (hs-CRP) levels were correlated with worsening of memory at 12 years follow-up. This data led the authors to conclude that “hs-CRP may be a useful biomarker to identify individuals at an increased risk for cognitive decline.”63 Likewise, in a study assessing over 4,000 subjects, higher levels of CRP and IL-6 were found to be associated with decreased cognition and executive function. IL-6 was also associated with steeper declines in memory performance during follow-up at up to five years.64

Another study found that, even in healthy individuals, baseline CRP levels were inversely correlated with the results of a learning and recall test at follow-up six years later. The investigators concluded that “relatively high concentrations of… CRP may be indicative for impaired cognitive performance.” 65 In a similar study, biological markers were measured in the blood of 93 healthy individuals aged 57 years (mean). At six years follow-up time, those individuals with the highest baseline CRP levels scored lower on a Word Learning test. In this study it was concluded that “concentrations of serum markers related to inflammation…are not only associated with Alzheimer's disease, but also with cognitive functioning in the cognitively healthy aging population.”66

The deleterious effects of inflammation on cognitive function are observable in real-time as well. Researchers administered a typhoid vaccination, which is known to induce an inflammatory response, or a placebo injection to 16 healthy men aged 18 to 35. Study subjects then completed a series of tests designed to assess cognitive vigilance. Participants who received the typhoid vaccination exhibited significantly slower reaction times than their counterparts who received the placebo, and the degree of delay in reaction time correlated with the intensity of inflammation, as measured by circulating IL-6 levels.67

Postoperative Cognitive Dysfunction

Acute confusion and impaired consciousness within a few days after major surgery is quite common, especially among older adults. This phenomenon is called postoperative delirium, and typically resolves before hospital discharge.454 Whether or not general surgery under anesthesia directly causes long term cognitive problems—termed postoperative cognitive dysfunction—is less clear. While there may be a true effect in some people, current evidence suggests that surgery and anesthesia are not robustly and directly linked to long-term cognitive impairment in most patients.455-457

Ongoing research has not found strong evidence of a link between persistent cognitive deficits and major surgery independent of overall health of the patient and their cognitive status trajectory before the surgery.457-459 Predisposing factors to worse cognitive outcomes after surgery include preexisting low-grade cognitive decline and early Alzheimer-type changes.456,460 The observational evidence linking surgery to cognitive decline is relatively weak, and rigorous study data suggest any true effect on long-term cognitive function is negligible.459,461 It may be that much of the apparent decline in cognitive function observed after surgery in older people is attributable to the post hoc ergo propter hoc fallacy— "after this, therefore because of this." But the expected continuation of a preexisting cognitive decline trajectory is thought to be the true culprit in many cases.457

One study found that, in pairs of middle-aged to elderly twins—who have very similar genetic and biochemical susceptibility—when one had undergone major surgery and the other had not, their cognitive scores were nearly identical. Another analysis in this study compared the twin who underwent surgery to a control group and found a small but clinically insignificant tendency to a lower cognitive score.459 In a meta-analysis that pooled data from 19 studies, no clear association was found between general anesthesia and dementia risk. Nevertheless, when the analysis was limited to studies that used records of anesthesia rather than subjective patient recall, the authors found a small increased risk of dementia in those who had received general anesthesia, highlighting the need for high-quality study designs when this phenomenon is studied in the future.461

The current lack of evidence does not mean that post-operative cognitive dysfunction is not worthy of a clinician's attention. Some studies have indeed found that surgery and general anesthesia are associated with negative effects on cognition in the elderly,462,463 negatively impacting the brain's immune system,463 and that post-operative cognitive dysfunction that persists three months after surgery is associated with an increased risk of dying from any cause.464 As surgical trauma induces a body-wide surge in inflammation, it has been proposed that inflammation of the brain, and failure to promptly resolve inflammation, may be causative factors for this syndrome. It has been proposed that measures to mitigate the trauma and inflammation resulting from major surgery may help prevent this problem.456,460

Novel treatments for preventing post-operative cognitive dysfunction (POCD) are currently under investigation. Perhaps one of the best-studied ones is ulinastatin, an enzyme-inhibiting agent that can be either synthesized or isolated from human urine.465 It is used in several Asian countries, but not yet approved in the United States.466 A 2016 review of the scientific literature found five randomized controlled trials examining intravenously-administered ulinastatin’s effect on POCD. In these trials, which enrolled a total of 461 elderly patients, ulinastatin reduced POCD compared to control treatment at three and seven days after surgery, but not on the day immediately following the procedure. Ulinastatin also reduced levels of the pro-inflammatory cytokine interleukin-6 within two days after surgery.467 A 2017 controlled clinical trial confirmed these results. In this study, 80 elderly patients receiving chemotherapy and undergoing radical esophagectomy were randomized to ulinastatin or a control group. Those in the ulinastatin group experienced less POCD seven days after surgery, an effect the authors hypothesized might have resulted from the observed lower levels of interleukin-6 and C-reactive protein, and higher levels of the protective cytokine interleukin-10.468

Two natural interventions have attracted attention for the prevention of POCD. In a randomized controlled trial, 61 patients aged 30‒70 years undergoing cardiopulmonary bypass received either 2 capsules of a Valeriana officinalis root extract per day or placebo. The intervention started a day before surgery and continued until 60 days after surgery. Subjects treated with the root extract had a significantly lower likelihood of POCD than those in the placebo group.469 A second intervention trial, underway as of mid-2018, is evaluating the potential of N-acetylcysteine as a treatment for POCD.470

Many of the integrative interventions discussed in this protocol that may help promote brain health may also help promote healthy postoperative cognitive function. Also, refer to the Surgical Preparation protocol, which reviews many integrative interventions that may support surgical recovery in general.

Hormonal Imbalance

Distributed throughout the brain are steroid hormone receptors which function to regulate the transcription of a vast array of genes involved in cognition and behavior.68 Adequate steroid hormone receptor activation in the brain is a fundamental determinant in many aspects of our lives that we take for granted. When hormonal imbalances or deficiencies disrupt receptor activation, cognitive deficits and emotional turmoil are the result.

Estrogen. Animal models indicate that experimentally-induced alterations in the levels of steroid hormones, particularly estradiol, in the brain cause significant behavioral changes observable within minutes, leading some researchers to conclude that steroid hormones actually have the capacity to function directly as neurotransmitters in the central nervous system.69 In humans, suboptimal (low) levels of estradiol are associated with decreased scores on standardized assessments of cognition in both men and women.70 Postmenopausal women with higher levels of endogenous estradiol also have better semantic memory than do those deficient in the estrogen.71 Accordingly, postmenopausal women treated with estradiol displayed improvements in executive function compared to those taking a placebo.72

Testosterone. Maintaining optimal levels of testosterone can help preserve cognitive ability as well. In a study involving over 500 aging men and women, higher levels of testosterone were linked with better performance on the Mini-Mental State Examination at baseline. Men with the lowest levels of testosterone at the beginning of the study period were more likely to exhibit a sharp decline in cognitive ability over the following two-year period as well.73 Several other studies also conclude that testosterone levels are positively associated with multiple aspects of cognitive function.74,75

Aging men given testosterone replacement therapy display improved cognitive function. In one study healthy men between the ages of 50 and 85 years responded to supplemental testosterone restoration treatment with significantly improved spatial and verbal memory, and spatial ability.76 Likewise, men with mild cognitive impairment or Alzheimer’s disease responded to testosterone therapy with enhanced spatial and verbal memory, and constructional abilities.77

Experimental studies indicate that the connection between testosterone and cognitive function is due in part to the dependence of the hippocampus on androgens to maintain synaptic density. Intriguing data shows that male non-human primates devoid of androgens have a dramatically reduced number of synapses in the hippocampus, which is of paramount importance for consolidation of short-term and long-term memory, as well as learning.78 Additional experimental data shows that hippocampal synaptic maintenance is androgen dependent.79

Dehydroepiandrosterone (DHEA). Age-associated decline in levels of the adrenal hormone dehydroepiandrosterone (DHEA), which is very active in the central nervous system,80 are also tied to worsening cognitive performance.81 In a study involving over 750 aging subjects, Mini-Mental State Examination (MMSE) scores were significantly associated with levels of DHEA-s, the sulfated metabolic derivate of DHEA, which is more highly concentrated in humans. Moreover, those individuals with the lowest levels of DHEA-s at baseline displayed greater cognitive decline over time than those with higher initial levels.82 In a separate community-based study involving nearly 300 healthy women, levels of DHEA-S correlated positively with superior executive function, concentration, and working memory.83 Accordingly, in a double-blind, placebo controlled clinical trial, six-months of supplementation with 25 mg of DHEA daily improved measures of cognitive function, especially verbal fluency, in aging women.84

Pregnenolone. Another neurosteroid, pregnenolone, is also involved with a number of cognition-related functions within the brain. For example, experimental studies indicate that pregnenolone modulates neurotransmitter signaling through interaction with select receptor sites, which translates to improvements in long-term memory in rodents.85,86 In human clinical trials, supplementation with pregnenolone improved cognition in subjects with neurological disorders.87 Additionally, levels of pregnenolone metabolites are reduced significantly in the prefrontal cortex, an area involved with higher-order processing, in Alzheimer’s disease patients, leading some researchers to speculate that pregnenolone levels may be relevant in the pathology of the disease.88

Research indicates that DHEA, pregnenolone, and metabolites thereof exert numerous activities in the central nervous system through activation of the Sigma-1 receptor. This effect may confer benefits including protecting neurons against ischemia (i.e. stroke),89 and enhancement of long-term potentiation (memory formation).90

Thyroid hormones. During the developmental period thyroid hormones play a critical role in ensuring proper growth and maturation of the brain.91 Thyroid hormone levels may also be related to cognitive function in adults, though the evidence in this area is inconsistent. However, limited associations with both hypo- (low) and hyper- (high) thyroid function and cognitive impairment exist in the peer reviewed literature, thus maintaining levels of TSH, T3, and T4 within normal ranges is suggested.92

The Aging Brain
Figure 2: Illustration showing the cerebrovasculature (bottom view of human brain)

Cerebrovascular Health

The brain depends on the carotid arteries to obtain the oxygen and nutrient-rich blood that it needs to sustain its high rate of metabolic activity. The carotid arteries emerge from the aorta and carry blood through the neck into the brain where they branch and diverge into many smaller capillaries, which facilitate circulation across the various brain regions. Like other blood vessels, the carotid arteries and their subsidiaries (smaller branches) are susceptible to endothelial dysfunction, dysregulation and damage to the delicate cells that line our blood vessels. Endothelial dysfunction is a critical step in both the initiation, and progression, of atherosclerosis.

If the integrity of the blood vessels that supply the brain is compromised, cognition suffers as a result. Multiple correlates between measures of vascular health and cognitive function are identified in the peer-reviewed literature.

HDL levels. HDL serves to shuttle cholesterol from the blood vessel walls back to the liver for excretion, and thus insufficient levels of HDL are associated with increased endothelial dysfunction and arterial plaque deposition. Studies have linked low HDL levels with declining brain health and function.

Researchers examined the brains of 183 subjects, mean age 58 years, using magnetic resonance imaging (MRI). Tests revealed that HDL levels were positively associated with brain grey matter volume. Not surprisingly, then, subjects with higher HDL levels also scored significantly higher on a visuo-spatial memory test than their counterparts with lower HDL levels. These findings lead the investigators to conclude that “adults with decreased levels of HDL cholesterol may be experiencing cognitive changes and grey matter reductions in regions associated with neurodegenerative disease and therefore, may be at greater risk for future cognitive decline.93

In a study of 139 very elderly subjects, plasma HDL levels were strongly associated with cognitive acuity. Subjects with higher HDL levels performed much better on the Mini-Mental State Examination (MMSE) than those with lower HDL levels. In fact, “each decrease in plasma HDL tertile (74.9 +/- 2.1, 50.6 +/- 0.5, and 36.8 +/- 1.0 mg/dl) was associated with a significant decrease in MMSE [score].94

Homocysteine. Homocysteine is an endogenous amino acid derivative which damages the endothelial cells that line the inside of blood vessels and contributes to the pathogenesis of atherosclerosis and vascular dysfunction.95 Elevated homocysteine has been linked with reduced blood flow to the brain,96 memory impairment,97 poorer global cognitive function,98 smaller overall brain volume,99 and increased silent brain infarcts (subclinical stroke-like blood vessel occlusions in the brain).100

In a randomized, placebo-controlled clinical trial, which included over 5,500 subjects with known cardiovascular disease, treatment with the homocysteine-lowering B vitamins folic acid (2.5 mg), B6 (50 mg) and B12 (1,000 mcg) was shown to significantly reduce the risk of stroke versus placebo, highlighting the link between cerebrovascular health and homocysteine levels.101

Similarly, lowering homocysteine in individuals over 70 years of age through supplementation with 800 mcg folic acid, 500 mcg B12, and 20 mg B6 daily for a period of 24 months was shown to reduce the rate of brain atrophy by 53% versus placebo control in a randomized, double-blind trial. Subjects receiving the homocysteine lowering B-vitamins also scored much better on their final cognitive tests at the end of the study period.102

Hypertension. Small, delicate capillaries, like those that perpetuate the flow of blood throughout the brain, are particularly susceptible to damage caused by elevated blood pressure. Chronic hypertension leads to the breakdown of cerebrocapillaries, a condition associated with the development neurodegenerative diseases and cognitive impairment.103

A case-control study of over 700 patients found a statistically significant correlation between blood pressure and rate of cognitive decline over a six-month period for subjects younger than 65 years.104 Accordingly, an observational study of more than 1,800 people revealed that individuals taking an antihypertensive medication were less likely to have dementia at the study onset, and were also less likely to develop dementia over the following three year period. Significantly, subjects who did have dementia at baseline and were not taking blood pressure medication exhibited a two-fold faster rate of cognitive decline than demented individuals with medication-controlled hypertension.105

In a study which followed 717 individuals for 38 years starting from age 45, researchers found that subjects with systolic blood pressure ≥140 mmHg throughout the study period “performed consistently less well than the normal systolic blood pressure subgroups on a composite measure of verbal learning and memory.”106

Evidence suggests that blood pressure of 115/75 mmHg significantly reduces the risk for cardiovascular disease,107 and thus may be an ideal target for those who wish to maintain optimal cognitive performance as well.

Diabetes and Insulin Resistance

Due to the high metabolic demand for energy in the brain, even small perturbations in glucose metabolism can noticeably impact cognitive performance. Diabetes (hyperglycemia) has been linked with lower levels of neuronal growth factors,108 decreased brain volume,109 and higher incidence of all types of dementia.110

Cerebral glucose metabolism was measured by fludeoxyglucose – positron emission tomography (FDG-PET) in 23 adults aged 74 years (mean), who met criteria for diabetes or pre-diabetes. The results were compared to those of six 74 year old (mean) adults without diabetes or pre-diabetes. Subjects were asked to memorize and recall a list of 20 random words they heard through a pair of headphones. FDG-PET scans revealed markedly different patterns of glucose utilization and brain activity between diabetic / pre-diabetic subjects and healthy controls during the memorization task. Subjects with healthy glucose metabolism remembered more words upon recall attempt. Interestingly, FDG-PET scans of those with pre-diabetes / diabetes resembled brain scans of Alzheimer’s patients.111

Researchers in another study compared MRI-assessed manifestations of cerebral degeneration in 89 non-demented subjects with type-2 diabetes to 438 age-matched healthy controls over a three-year period. Individuals with diabetes displayed increased progression of brain atrophy, and performed less well on tests of cognitive performance and learning. The investigators concluded that “our data show that elderly patients with [type-2 diabetes] without dementia have accelerated progression of brain atrophy with significant consequences in cognition compared to subjects without [type-2 diabetes]. Our findings add further evidence to the hypothesis that diabetes exerts deleterious effects on neuronal integrity.”112

In over 1,300 aging men, researchers observed an inverse correlation between fasting insulin levels and cognitive function in non-diabetics. Baseline insulin levels were assessed and followed by a battery of cognitive testing an average 3.3 years later. Subjects with higher initial insulin levels scored more poorly on all four tests administered. These results indicate that “higher fasting insulin and greater insulin secretion in older men may be related to overall cognitive decline, even in the absence of diabetes.”113


Adipose tissue secretes molecules that directly influence multiple functions within the brain.114 There is a clearly established reciprocal relationship between adiposity (amount of body fat) and overall brain volume and cognitive function. In other words, as bodyweight increases, brain volume drops and cognitive function worsens.115,116,117,118

In a study utilizing MRI brain imaging technology to explore the link between obesity and brain volume, researchers discovered that visceral abdominal obesity in particular was associated with deteriorating brain structure. This was true even in individuals without pre-existing cognitive deficits. The findings were statistically significant and independent of vascular risk factors and overall BMI. 119

Similar findings were reported by another group, but this time in 700 patients with a prior diagnosis of Alzheimer’s disease or cognitive impairment. Investigators identified a strong correlation between higher BMI and brain volume deficits in the frontal, temporal, parietal, and occipital lobes. It was concluded that “cardiovascular risk factors, especially obesity, should be considered as influencing brain structure in those already afflicted by cognitive impairment and dementia.”120

In 90 healthy middle-aged and older adults (ages 54 – 81), who performed tests of manual dexterity, motor speed, and executive function, greater central obesity as manifested by higher waist circumference was associated with poorer performance. Not surprisingly, high blood pressure exacerbated the correlation between increasing waist circumference and declining cognition; “in healthy older adults, there are similar, negative relations of central and total obesity to cognitive function that are potentiated by higher [blood pressure] levels.”121

Mid-life obesity was strongly linked to later-life dementia in over 1,000 participants in a longitudinal study carried out over a 36 year period. Subjects with the greatest waist diameters at baseline were nearly three-fold more likely to develop dementia over the following three decades. The investigators in this study concluded that “central obesity in midlife increases risk of dementia independent of diabetes and cardiovascular comorbidities.”122