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Protective Effects of Exercise on Cognition and Brain Health in Older Adults

Tyndall, Amanda V.1,2; Clark, Cameron M.1,2; Anderson, Todd J.3,4; Hogan, David B.2,5,6,7; Hill, Michael D.2,5,6; Longman, R.S.2,8,9; Poulin, Marc J.1,2,4,5,10,11

Exercise and Sport Sciences Reviews: October 2018 - Volume 46 - Issue 4 - p 215–223
doi: 10.1249/JES.0000000000000161
Articles
Journal Club

Accelerated trajectories of cognitive decline in older adults may increase the risk of developing Alzheimer disease and related dementias (ADRD). Physical activity has potential modifying effects on these changes that could prevent or delay ADRD. This review explores the hypothesis that multiple, mutually complimentary, and interacting factors explain the positive association between exercise and the optimization of cognition in older adults.

The role of physical activity and the interplay between physiological biomarkers and psychological and lifestyle factors on cognitive aging.

1Department of Physiology & Pharmacology,

2Hotchkiss Brain Institute,

3Department of Cardiac Sciences,

4Libin Cardiovascular Institute of Alberta,

5Departments of Clinical Neurosciences,

6Community Health Sciences,

7Medicine, and

8Psychology, University of Calgary;

9Psychology Service, Foothills Medical Centre, Alberta Health Services;

10Faculty of Kinesiology, University of Calgary, and

11O’Brien Institute for Public Health, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

Address for correspondence: Marc J. Poulin, Ph.D., DPhil, Department of Physiology & Pharmacology, Brenda Strafford Foundation Chair in Alzheimer Research. Cumming School of Medicine, University of Calgary HMRB-210, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada(E-mail: poulin@ucalgary.ca).

Accepted for publication: June 21, 2018.

Editor: Demetra D. Christou, Ph.D.

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Key Points

  • Postmaturation aging is accompanied by many adverse changes including physiological measures (i.e., decreases in physical fitness and cerebrovascular function), biomarkers (i.e., increases in oxidative stress), and psychological (i.e., mood changes) and lifestyle (i.e., smoking and alcohol use) factors.
  • These factors have been shown to influence the trajectory of age-associated cognitive decline and the risk of developing Alzheimer disease and related dementias (ADRD).
  • Lifestyle interventions such as exercise have been shown to have potential modifying effects on these changes that could prevent or delay ADRD.
  • Approximately 60% of older adults do not engage in enough physical activity and exercise to promote maintenance or improvements in their overall cognitive and brain health.
  • This review builds on a previous journal contribution and other research published by our group that aims to advance knowledge of the mechanisms by which exercise improves cognition in older adults.
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INTRODUCTION

We live in an aging world. It is estimated that by the year 2024, older adults (i.e., those aged 65 years and older) will account for 20.1% of the Canadian population, up from the current 16.1% (1). Increasing age is strongly associated with the development of dementia, particularly from Alzheimer disease (AD) and other neurodegenerative causes. Dementia is characterized by the presence of significant cognitive decline to the point where independence in everyday activities becomes affected. There are multiple potential causes, with AD the most common. At autopsy, most of those with dementia will have evidence of Alzheimer or vascular pathologies. A more comprehensive understanding of the mechanisms underlying the development of dementia will aid in developing effective interventions to promote healthy brain aging. Even with our current imperfect understanding, there is hope that we can bend the incidence curve and prevent many future cases. The Lancet Commission on dementia recently concluded that up to 35% of all cases may be attributable to nine potentially modifiable risk factors including education, hypertension, obesity, hearing loss, smoking, depression, physical inactivity, social isolation, and diabetes (2). Because of the frequent synergistic interaction between vascular and Alzheimer pathology in producing the dementia phenotype, it is important to develop a better understanding of the contributions of vascular disease to neurodegenerative causes of dementia (3).

The World Health Organization has identified physical inactivity as the fourth leading risk factor for mortality. Physical inactivity has been recognized as a modifiable risk factor for cardiovascular disease, type 2 diabetes, and obesity. Successfully promoting increased physical activity, such as by engaging in regular aerobic exercise, has the potential to reduce the number of people who will develop a variety of age-associated diseases.

While the potential beneficial effects of exercise on cognition and brain health in older adults are well established, the mechanisms underlying this association remain incompletely understood. This review will examine the central hypothesis that multiple, mutually complementary and interacting factors are at play to optimize cognition and brain health in older adults (Figure). Furthermore, this review will examine the interplay between these factors and will explore the novel hypothesis that the beneficial effects of exercise on cognition are explained, at least in part, by changes in cerebrovascular function (e.g., basal cerebral blood flow, cerebrovascular reserve). Finally, we will review recent evidence suggesting the existence of a dose-dependent relation between exercise intensity and improved cognition and brain health in older adults.

Figure

Figure

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COGNITIVE CHANGES WITH AGING

Normal Aging

Crystallized intelligence includes tasks that are overlearned, frequently practiced, and familiar to the person. Examples include vocabulary, visuospatial abilities (e.g., object perception, recognition of familiar objects, spatial perception), and general knowledge. These abilities typically remain stable or may gradually improve as we age, in the absence of disease. Fluid intelligence, in contrast, is the ability to problem-solve and reason about novel situations. This is independent of what has been learned and includes the ability to process new information, solve novel problems, as well as attend to and manipulate one’s environment. Executive functions (i.e., abilities that allow a person to engage in independent, appropriate, purposive, and self-directed behavior), processing speed (i.e., rapidity in performing cognitive and motor activities), attention (i.e., ability to concentrate and focus), and declarative memory (i.e., conscious recollection of facts and events) are categorized as fluid domains. Commonly but not universally, with aging, there is slowing of processing speed (starting in the third decade), impairments in complex attention tasks (i.e., selective and divided attention), declines in declarative memory (especially of episodic), deterioration in visual construction skills (i.e., ability to put together individual parts to make a coherent whole), and deleterious changes in certain executive functions (e.g., concept formation, abstraction, mental flexibility, response inhibition). It is important to note that these age-associated changes are generally subtle and variable, with significant between-individual heterogeneity in the rate of decline (4). They typically do not interfere with an aging person’s ability to engage in everyday activities.

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Subjective Cognitive Complaints

Subjective cognitive complaints, usually involving memory, with normal performance on cognitive testing for age, sex, and education are common among healthy older adults. A moderate correlation has been observed between studies for objective cognitive performance and concurrent subjective complaints. The causes and implications of this observation are uncertain. It is possible that those with subjective complaints are either showing subtle changes not detectable on the tests or experiencing individualized decline over time that cannot be shown in cross-sectional data. They also may be more sensitive to expected age-related changes in cognition because of their psychological make-up. A longitudinal study of older individuals found no relation between the levels of cognitive functioning and complaints but a substantial one between changes in functioning over time and the level of complaints, suggesting that perceived change over time is the major driver (5). Results from studies evaluating the risk of future mild cognitive impairment (MCI – please see next section) or dementia among those with subjective cognitive complaints are not consistent. The ability of physical activity to reverse subjective cognitive complaints also is unresolved in the literature. Although, a 12-week exercise intervention in older adults with subjective memory complaints showed improvements in test of verbal memory, attention, and executive function (6).

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Mild Cognitive Impairment

Approximately 12%–18% of older adults have more than expected cognitive decline with aging but do not meet criteria for dementia. This intermediate state between normal aging and dementia is called mild cognitive impairment (MCI). It is described as ‘amnestic’ when an objective memory deficit is present, or ‘nonamnestic’ if the cognitive decline does not include memory concerns (7). Although MCI is a high-risk state for the development of AD and other dementias, not all persons with MCI develop dementia. Approximately 10%–15% per year of those with MCI will evolve into a dementia (8).

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Alzheimer Disease and Related Dementias

Dr. Alois Alzheimer was the first to examine the postmortem brain of a woman with a number of unusual microscopic changes that included tangled bundles within neurons (neurofibrillary tangles) and the deposition of a “peculiar substance” (now known as amyloid plaques) between them. The neurofibrillary tangles and amyloid plaques are now recognized as pathological hallmarks of AD that precede, by years if not decades, the onset of clinical symptoms (9). NIA-AA diagnostic criteria for probable AD dementia require the presence of a dementia with an insidious onset and clear-cut evidence of progression over time (9). There should be no other likely cause of cognitive dysfunction. An amnestic presentation with impairment in learning and recall of recently learned material is the one most commonly encountered.

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Vascular Cognitive Impairment

Vascular cognitive impairment (VCI) refers to all forms of cognitive impairment associated with and presumed due to cerebrovascular disease. It includes people who have vascular MCI, mixed dementias where cerebrovascular disease in addition to another pathology (usually Alzheimer disease) is felt to be making a substantial contribution to the dementia, and vascular dementia. Studies have shown that vascular disease and Alzheimer changes are major pathological correlates of cognitive decline in later life (10). VCI can arise from a variety of vascular pathologies such as atherosclerosis or microvascular disease, for example from cerebral amyloid angiopathy. A single ischemic and hemorrhagic stroke can lead to dementia if key structures, such as the medial thalamus or bilateral temporal lobes, are damaged. Global cognitive impairment can arise from progressive small infarcts in the subcortical white matter. VCI is a broad concept for all forms of cognitive impairment associated with cerebrovascular disease and would include both pure vascular disease and cases of mixed pathologies. The likelihood of a causal relation between the noted cerebrovascular disease and the cognitive symptoms is strengthened by a clear temporal relation between a vascular event and the onset (or worsening) of the cognitive deficits and not obtaining a history of progressive decline prior to the vascular event, which would be suggestive of a contributing neurodegenerative cause (10).

Vascular disease is linked to the evolution of amyloid plaques. Individuals with Alzheimer pathology have a far greater risk of developing clinical dementia if they suffer a concurrent stroke. Vascular disease may be the most preventable contributing cause of dementia and amenable to interventions such as diet, exercise, and management of vascular risk factors such as dyslipidemia, hypertension, or atrial fibrillation (10).

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PROPOSED MECHANISMS UNDERLYING COGNITIVE DECLINE WITH AGING

The proposed mechanisms, clustered in categories, are depicted in the Figure. This section will discuss each category and its components in relation to cognitive aging. We will emphasize the potential influence of physical activity on mitigating noted deleterious effects.

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Biomarkers

Biomarkers are defined as “a biological characteristic that is objectively measured and evaluated as an indicator of normal biological or pathological processes, or a response to a therapeutic intervention” (11). In this review, we use the term biomarkers “in the general sense” and not in a restricted manner (i.e., limited to variables from magnetic resonance imaging/positron emission tomography (PET) and cerebrospinal fluid proteins). There is an intense search for peripheral serum or plasma biomarkers of AD and other dementias.

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Inflammatory markers

Chronic low-grade inflammation is commonly seen in aging and is associated with an increased risk of the development of age-related pathologies such as cardiovascular disease (CVD). Circulating plasma proinflammatory markers broadly include inflammatory cytokines (e.g., interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα)), acute phase proteins (e.g., C-reactive protein (CRP)), and coagulation factors. There is increasing evidence of an association between adverse neurocognitive aging, including AD and low-grade inflammation, possibly through mechanisms such as neuronal death, neurotransmitter dysregulation, and blood-brain barrier dysfunction (12).

Studies have consistently shown a robust association between higher levels of physical activity and lower levels of inflammatory markers in older adults. However, the response of the immune system to exercise depends on the intensity, duration, and frequency of exercise. A 12-week supervised combined aerobic and resistance training intervention had an increase in estimated cardiorespiratory fitness, and an 11% decline in CRP levels postintervention independent of any weight loss in previously inactive healthy older adults (13). Although there were no differences in CRP levels before the intervention between inactive and active older adults in this study, others have observed that those who report (via interviewer-administered questionnaire) being more physically active had lower levels of CRP, IL-6, and TNF-α (14). Collectively, these studies demonstrate the potential importance of physical activity in attenuating age-related increases in measures of chronic low-grade inflammation that might have downstream positive influences on brain aging.

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Growth factors

In older adults, growth factors (or neurotrophins) are essential for continued brain development, maintenance of existing neurons, neurogenesis, and brain plasticity while also being neuroprotective in the face of insults. It has been long known that the secretion of growth factors such as growth hormone (GH), insulin-like growth factor-1 (IGF-1), brain-derived neurotropic factor (BDNF), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) declines with increasing age. Physical activity has been shown to upregulate their release and, in some cases, receptor availability (15).

The most robust findings in humans on the upregulation of neurotrophins in response to physical activity has been observed in IGF-1, BDNF, and VEGF. Physical activity-dependent increases in peripheral IGF-1and VEGF levels can cross the blood-brain barrier and stimulate angiogenesis and neurogenesis, specifically in the hippocampus (16). Increased aerobic exercise, and increases in maximal aerobic capacity (V˙O2max), also has been shown to improve BDNF and IGF-1 levels within the hippocampus (17). These improvements in BDNF and IGF-1 levels are positively associated with increased hippocampal size and spatial memory performance in older adults (17). From these studies, it has been hypothesized that IGF-1, VEGF, and BDNF work together to improve spatial memory (and potentially other cognitive functions) through improved hippocampal function by mechanisms such as neurogenesis and angiogenesis.

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Cardiometabolic risk factors

Risk factors for cardiovascular disease (CVD) include dyslipidemia, hyperglycaemia due to insulin resistance, abdominal adiposity, hypertension, and low levels of high-density lipoprotein (HDL). Collectively, these risk factors make up the components of the metabolic syndrome (MetS), which is associated with an increased risk of type 2 diabetes mellitus, stroke, atherosclerosis, obstructive sleep apnea, depression, liver disease, and chronic kidney disease. The prevalence of MetS increases with age and physical inactivity. This is an increasing public health concern due to both population aging and rising levels of obesity. Interestingly, medications for hyperlipidemia (i.e., statins) were the most commonly prescribed medications in a Canadian sample of sedentary but otherwise healthy older adults (18). This also is seen in the entire Canadian population of older persons (18). These studies highlight the high prevalence of vascular risk factors in the Canadian population and the use of prescribed medications for this indication.

MetS also is associated with worse cognitive functioning, may accelerate the trajectory of cognitive decline, and increase the likelihood of developing AD or other dementias (19). Memory, spatial abilities, processing speed, and executive functions seem to be the most sensitive cognitive functions to changes in cardiometabolic status. In cognitively healthy older adults, a study found a 15% reduction in cerebral blood flow (CBF) in those classified with MetS, that correlated with lower immediate memory scores (20). Physical activity is widely endorsed as a way of improving metabolic function. Early detection of MetS or individual cardiometabolic risk factors, followed by early aerobic exercise intervention to prevent these risk factors from influencing the vascular system, may have a favorable impact on cognitive decline in aging.

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Oxidative stress

The signaling cascades associated with reactive oxygen species (ROS) have received attention for their role in the aging process. The oxidative stress hypothesis of aging posits that the declines seen with it are due to the accumulation of oxidative damage (21). ROS are considered toxic byproducts of cellular metabolism that is required for oxidation–reduction reactions, signal transduction, and cellular survival.

Physical activity may modify control oxidative stress-related damage in older adults, through mechanisms such as increasing nitric oxide (NO) bioavailability and modifying age-related changes in endothelial shear stress (22). In a study of healthy older women, higher mean arterial pressure and lower cerebrovascular conductance and NO levels were correlated with higher levels of oxidative stress (22). In addition, women who were more physically fit (i.e., higher V˙O2max) had higher activity of antioxidant enzymes and lower oxidative stress levels (22). The healthier vasculature measures seen with higher levels of physical fitness may be partly due to decreases in oxidative stress.

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Genetic risk

Our genetic makeup influences survival and the relationships between aging and physiological changes and the development of age-associated disease such as AD. There has been interest in identifying the nonmodifiable genetic risk factors associated with the development of late-onset Alzheimer disease (LOAD). Although numerous genetic variants have been associated with the development of AD, apolipoprotein E (APOE) allele ε4 is the most studied genetic variant related to LOAD. Carriers of one ε4 allele have a 2.5-fold increased risk of LOAD by certain ages, whereas carriers with two ε4 alleles have a 16-fold higher risk (23). The APOE ε4 allele is a genetic risk factor for sporadic (or late onset) cases of AD. Early onset AD may be associated with rare genetic variants.

Epigenetic changes (specifically DNA methylation patterns) that occur in humans vary in response to regular aerobic exercise. However, the associations between common single-nucleotide variants in risk genes for AD or vascular disease and the potential modulating effects of exercise are not well understood. Further studies are needed.

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Physiological Factors

All physiological processes are affected with normal aging. Age-associated changes include an increase in cell death, slowing of cell regeneration and tissue repair after injury, decreased neuromuscular actions, and degeneration of the nervous system. In this section, we will discuss the changes in the cerebrovascular system, brain structures, and cardiorespiratory fitness with normal aging and their association with neurocognitive impairment.

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Cerebral blood flow and cerebrovascular reserve

As reported in a previous Exercise and Sport Sciences Reviews article, postmaturational aging is associated with a decline in resting CBF of approximately 5% per decade (24). PET images have revealed that in normal aging, the brain regions that show greater decline in resting CBF are principally association areas, such as the medial frontal regions, and the limbic cortices (25). They are important for controlling cognitive processes such as learning and memory, executive function, and attention (25). There also is a decline in cerebrovascular reserve, which is the ability of the cerebral blood vessels to dilate in response to a change in metabolic demand or a stimulus (24,26). With increasing age, decreased CBF and cerebrovascular reserve may lead to long-term hypoperfusion, increasing the risk of cognitive dysfunction and dementing illnesses (24). Accumulating evidence suggests that changes in CBF are indicative of vascular insults that occur before the onset of symptomatic AD or other pathologies (24). However, it remains uncertain whether AD is a cause of hypoperfusion or, conversely, if hypoperfusion may contribute to the development of AD.

Cerebrovascular conductance (CVC) is a measure of vascular tone in which cerebral blood flow is divided by mean arterial pressure (27). CVC has been shown to be negatively correlated with age at rest, during low- to moderate-intensity submaximal exercise, and in recovery from submaximal exercise (28). In a second study, although CVC was similar at rest between younger and older adults, it was lower for the older adults during submaximal exercise (50% heart rate reserve) (29). Taken together, these results indicate that when the vasculature is given a stimulus, blood flow response is blunted in healthy older adults compared with younger adults.

It also seems that MetS and its components influence the brain through observed changes in cerebrovascular function (30). Healthy older adults who were classified as having MetS had lower blood flow velocity (

P) and CVC through the middle cerebral artery (MCA) (30). In addition, vascular reactivity to a carbon dioxide challenge is compromised in those with MetS (30).

Chronic aerobic exercise has repeatedly been observed to be associated with preserved (i.e., no age-related decline) or slightly higher CBF in older adults. In a study of healthy older women with no cognitive impairment, those with higher levels of aerobic fitness had higher CVC in the MCA and lower mean arterial pressure (MAP) (28). A 12-week aerobic exercise intervention increased cerebrovascular reactivity to hypercapnia in the MCA in both older (mean age 63) and younger participants (mean age 23) (31).

Links between cerebrovascular function and cognitive health have been observed in a sample of healthy older adults where cerebrovascular function was found to partially mediate the relationship between physical fitness (i.e., V˙O2max) and global cognitive performance (32). It seems that the influence of physical fitness on cognitive function may be mediated (at least in part) by improvements in cerebrovascular function.

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Brain structure

Structural changes of the brain with increasing age are not uniform across all brain regions or individuals. In healthy older adults without dementia, hippocampal volume decreases by approximately 1%–2% per year. The hippocampus is an important brain structure crucial for memory functions. Memory is typically the earliest affected domain of cognition in MCI (17). Cross-sectional studies reveal that healthy older adults also have smaller prefrontal, neostriatal, hippocampal (medial temporal), and cerebellar regions than healthy younger adults. It seems that these age-vulnerable brain regions begin to atrophy by the third decade of life. Furthermore, longitudinal studies have repeatedly found whole-brain shrinkage across time (33). These age-associated brain structural changes are felt to be a manifestation of genetic, physiological, and disease-related mechanisms.

Aerobic exercise in healthy older adults (without dementia) has been associated with increases in grey and white matter volumes in both temporal (including the hippocampi) and prefrontal regions (17). Increased hippocampal volume also was observed after a six-month aerobic exercise intervention in women with probable MCI (34). These studies demonstrate potential plasticity of the hippocampus in response to exercise in older age, even among those affected by MCI.

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Maximal aerobic capacity and physical inactivity

With increasing age, there is a slow and progressive decline in physical fitness as measured by maximum aerobic capacity (V˙O2max). Among sedentary adults, V˙O2max declines by approximately 10% per decade of life. To carry out activities of daily living and remain independent, V˙O2max should not drop below 1.0 L/min (or 15 mL/kg/min) (35). In addition, with every 1 metabolic equivalent (MET; MET = V˙O2max [mL/kg/min]/3.5), drop in overall fitness, there is a 12% increase in mortality risk (35). Even though some age-related decreases in V˙O2max are inevitable, much of the change seen with aging in V˙O2max can be attributed to declining physical activity and changes to the cardiovascular system. Regular physical activity in older age can help to preserve V˙O2max and overall cardiovascular health (35).

Cognitive abilities are better maintained in older adults who engage in higher levels of physical activity and have higher V˙O2max (28). In a sample of 226 healthy older adults with no cognitive impairment, global cognitive performance was associated with higher self-reported total lifetime physical activity levels, recreational physical activity, and vigorous-intensity exercise (32). Interestingly, it seems that higher levels of physical activity between childhood and age 35 years was more strongly associated with better global cognitive performance, compared with physical activity levels at older ages (32). Similar results were found in a sample of adults older than 65 years, where higher engagement of self-reported leisure activities was associated with a decreased risk of incident dementia (36). From these, and other longitudinal studies, it has been shown that lower levels of cardiorespiratory fitness and cognitive performance in early adulthood are associated with higher MCI and dementia risk later in life (37).

Self-report measures of physical activity have to be used with caution because they can be influenced by recall bias and social desirability (i.e., reporting as much physical activity as they think one should report). Actigraphy is a method of measuring active energy expenditure and rest cycles, and has become a popular method of noninvasively measuring objectively daily physical activity. In a study of 716 older adults without dementia at baseline, higher levels of physical activity as measured by actigraphy predicted a lower risk of developing AD over the four years after the baseline assessment (38). This study also demonstrated that total daily levels of physical activity were associated with cognitive functioning at baseline and the rate of cognitive decline shown at follow-up testing (38). Self-reported and objectively measured physical activity predict cognitive function, cognitive decline associated with aging, and risk of AD (39).

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Psychological and Lifestyle Factors

Psychological factors have been observed to influence cognition and serve as predictors of cognitive decline in aging. Specifically, depression and anxiety can affect psychological wellbeing and the quality of life of older adults. This section describes psychological factors and modifiable lifestyle factors (i.e., risk factors) that influence successful brain aging.

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Mood

Mood can be conceptualized as the balance between 1) positive affect, including states of joy, vigor, and alertness; and 2) negative affect, including states of dissatisfaction and unhappiness. In participants with normal cognition or MCI, baseline depressive and anxiety symptoms (i.e., indecision, worry, and social withdrawal) predicted AD at the time of a three-year follow-up assessment (40). From this study, it was hypothesized that depressive symptoms could be a preclinical manifestation of AD whereas anxiety may be a response to neurocognitive degeneration (40).

Improvements in mood have been demonstrated with engagement in regular physical activity (for review see (41)). Specifically, exercise reduces tension, depressive symptoms, and anger while leading to positive changes in perceived vigor and fatigue (41).

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Sleep

There is increasing evidence of a bidirectional relationship between sleep and AD (42). Chronic adverse changes in sleep including increased sleep onset, poor sleep efficiency, and increased awakenings during the night are both common and can impair normal daily functioning in older adults. It has been postulated that during normal sleep, there is removal of neurotoxic waste products (e.g., Aβ) that accumulate while awake as byproducts of neural activity. Because one of the hallmarks of AD pathology is the aggregation of Aβ deposits, it has been proposed that normal sleep may be protective against AD (42).

Carriers of the APOE ε4 allele had poorer objective sleep (as measured by actigraphy) but no difference in subjective sleep complaints compared with noncarriers in a recent study (42). The worse sleep quality in APOE ε4 carriers was due to decreased sleep efficiency and increased amount of time spent awake after sleep onset (42).

Chronic aerobic exercise intervention studies have shown improved sleep quality on both subjective and objective measures in older adults with sleep complaints. For example, in a group of 79 sedentary but otherwise healthy middle-aged and older (>50 years) adults, higher physical activity (as measured by actigraphy) was associated with less time awake after sleep onset and higher sleep quality (43). These and other studies demonstrate a bidirectional relationship between sleep and AD risk, as well as between sleep and physical activity (43). With increasing age, sleep quality decreases that possibly leaves the brain more vulnerable to neurotoxic effects. It has been repeatedly demonstrated that physical activity improves sleep quality in healthy older adults.

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Cognitive activity

Numerous studies have demonstrated that cognitive activity is associated with a person’s cognitive performance and subsequent risk of developing of dementia and AD (44). In a group of 42 cognitively healthy postmenopausal women, a greater number of cognitive activities but not time spent on them significantly predicted better global cognitive performance after controlling for demographics, physical fitness (V˙O2max), and vascular health (44). Adults older than 70 yr who engaged in computer use, crafts, playing games, and socializing were found to have a significant lower risk of developing MCI. Engagement in cognitive activities was specifically shown to improve working memory, perceptual speed, attention, and executive function domains (44). It has been proposed that repetition of cognitive activities enables domain-specific brain functions to become more efficient and possibly vulnerable to age-related changes and AD pathology (44).

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Diet

The positive effects of diet on cognitive functioning are likely mediated in part through the cardiovascular system. A heart-healthy diet with low glycemic load food is not only beneficial for the cardiovascular system but also the brain (45). The Mediterranean diet consists of a high intake of vegetables, fruits, legumes, and cereals, a moderate intake of wine and fish, and a low intake of saturated fats (olive oil being the primary source of fat), dairy, or red meat. Adherence to it is associated with a reduced risk of mortality from a number of age-related conditions including cardiovascular disease, stroke, type 2 diabetes mellitus, MetS, and cognitive decline (46). It also seems that adherence to the Mediterranean diet may protect against global cognitive decline in those without dementia. It is unclear what components might lead to this possible benefit. The consumption of fish oils containing the omega-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EHA) was associated with reduced risk of dementia and reduced cognitive decline in a study (46). This is possibly through a reduction in triglycerides, an improvement in CBF, or reduced proinflammatory cytokines and amyloid aggregation. With a Mediterranean diet, the intake of polyphenols – which are found in many foods including fruits (especially berries), vegetables, red wine (specifically resveratrol), chocolate, coffee, and tea – likely increases (46). Polyphenols have been found to have anti-inflammatory and antioxidant properties (46).

With respect to the recombined influence of physical activity and diet on health, these is some evidence suggesting that a combined physical activity and eating a healthy diet lifestyle is associated with better health outcomes such as lower LDL cholesterol, lower waist circumference, and mean arterial pressure than diet or physical activity alone (47).

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Smoking and alcohol use

Smoking and heavy alcohol use are modifiable factors associated with an increased risk of mortality (48). Cigarette smoking negatively influenced cognitive functions such as processing speed and cognitive flexibility in middle-aged adults when assessed at a 5-year follow-up (48). In another population-based longitudinal study of healthy cognitively intact older adults (>55 years), smoking was associated with a doubling of the risk of AD (49).

Moderate alcohol consumption in some studies seemed to lower risk for the development of coronary heart disease and thrombotic stroke (50). Among adults aged 35–69 years, cardiovascular-related mortality was 30%–40% lower in those who consume one drink daily but increased in heavier consumers (50). This may be subject to further elaboration because a recent report found that alcohol consumption, even at moderate levels, was associated with adverse brain outcomes including hippocampal atrophy (51).

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EXERCISE PRESCRIPTION CONSIDERATIONS

Adherence to Exercise

Although many older adults recognize that physical activity is beneficial for healthy lives, most do not engage in enough physical activity to attain these benefits, which are only gained from continued and sustained participation in a program of sufficient intensity and frequency. Structured exercise or group-based exercise programs may provide the most benefit for older adults because adherence tends to be better in these types of programs (52). These activities should be both enjoyable and capable of leading to objective gains in endurance or V˙O2max.

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Exercise Dose

The American Heart Association and the American College of Sports Medicine (ACSM) have both established recommendations for the dosage of exercise required for cardiovascular and respiratory health (53). However, the particular dose of exercise required for the maintenance of brain and cognitive health, particularly in older adults, is not known. Determining thresholds for brain and cognitive benefit based on existing exercise trials in older adults remains difficult because of differences in prescribed exercise intensity and duration, differences in risk factors (i.e., age, sex), and variation in adherence to these prescriptions by the participants themselves. Indeed, preliminary data from our laboratory suggest that not all participants are able to reach an intended level of exercise intensity or duration, even among healthy older adults aided by considerable monitoring and encouragement throughout the exercise intervention. Ongoing work from our laboratory is seeking to characterize heterogeneity in adherence to exercise intensity and duration prescriptions, by mapping individual exercise dose trajectories over the course of a 6-month intervention. By grouping similar trajectories together via novel statistical approaches, we can begin to understand the underlying physiological (e.g., cerebrovascular function, V˙O2max), and even psychological (mood states) characteristics of participants, which may predict or otherwise account for the ability to achieve doses of exercise likely to benefit brain health and cognitive performance in older age. Furthermore, understanding which variables predict success or failure in reaching a prescribed exercise dose has enormous implications in crafting personalized recommendations to optimize benefit from maximally tolerable exercise doses.

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Types of Physical Activity Interventions and Social Engagement

Many different modes of physical activity have been evaluated for their influence on cognitive functioning in older adults. Although aerobic exercise has been the type used most often, Tai Chi or Qigong, resistance training, and contemporary or social dance have all shown at least some improvement in certain cognitive function.

Older adults are more likely to be adherent in an exercise program if they are participating in an activity with a spouse or friend. The social engagement provided by an intervention study also could influence downstream cognitive functioning. Older adults who engaged in more cognitive, physical, and social activities over three years had a decreased risk of developing dementia. Coupling physical activity with challenging cognitive tasks and increased opportunities for socialization will likely lead to greater benefit than if one approach is used as the sole intervention.

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CONCLUSIONS

In conclusion, physical activity, particularly aerobic exercise, through a number of mechanisms has the potential to support brain health as we age (Figure). In addition to benefits on the cardiovascular system, physical activity has positive effects on blood biomarkers, physiology, and psychological factors associated with cognitive functioning. Physical activity is a modifiable lifestyle change that could prevent or delay age-associated diseases including dementia. We suspect exercise has its beneficial impact through multiple mechanisms that together promote healthy brain aging. Multicomponent interventions that combine physical activity with mental stimulation and socialization hold particular promise. Collaboration between basic scientists, clinicians, and older community volunteers will be needed to fully understand this complicated but potentially fruitful area of research and help older adults live their fullest, healthiest lives.

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Keywords:

exercise dose; cerebrovascular function; cognitive function; aging; intervention

© 2018 American College of Sports Medicine