Elsevier

Mayo Clinic Proceedings

Volume 86, Issue 9, September 2011, Pages 876-884
Mayo Clinic Proceedings

Special Article
Physical Exercise as a Preventive or Disease-Modifying Treatment of Dementia and Brain Aging

https://doi.org/10.4065/mcp.2011.0252Get rights and content

A rapidly growing literature strongly suggests that exercise, specifically aerobic exercise, may attenuate cognitive impairment and reduce dementia risk. We used PubMed (keywords exercise and cognition) and manuscript bibliographies to examine the published evidence of a cognitive neuroprotective effect of exercise. Meta-analyses of prospective studies documented a significantly reduced risk of dementia associated with midlife exercise; similarly, midlife exercise significantly reduced later risks of mild cognitive impairment in several studies. Among patients with dementia or mild cognitive impairment, randomized controlled trials (RCTs) documented better cognitive scores after 6 to 12 months of exercise compared with sedentary controls. Meta-analyses of RCTs of aerobic exercise in healthy adults were also associated with significantly improved cognitive scores. One year of aerobic exercise in a large RCT of seniors was associated with significantly larger hippocampal volumes and better spatial memory; other RCTs in seniors documented attenuation of age-related gray matter volume loss with aerobic exercise. Cross-sectional studies similarly reported significantly larger hippocampal or gray matter volumes among physically fit seniors compared with unfit seniors. Brain cognitive networks studied with functional magnetic resonance imaging display improved connectivity after 6 to 12 months of exercise. Animal studies indicate that exercise facilitates neuroplasticity via a variety of biomechanisms, with improved learning outcomes. Induction of brain neurotrophic factors by exercise has been confirmed in multiple animal studies, with indirect evidence for this process in humans. Besides a brain neuroprotective effect, physical exercise may also attenuate cognitive decline via mitigation of cerebrovascular risk, including the contribution of small vessel disease to dementia. Exercise should not be overlooked as an important therapeutic strategy.

Section snippets

REGULAR EXERCISE AS NEUROPROTECTIVE THERAPY

Although medications have no proven neuroprotective effect on dementia, an evolving literature documents significant benefit of long-term, regular exercise on cognition, dementia risk, and perhaps dementia progression. These studies suggest an attenuating effect on brain aging and resilience to dementing neurodegenerative mechanisms.

Exercise also favors brain health via the well-known attenuating influences on atherosclerotic cerebrovascular disease. Thus, primary vascular dementia is common

DEFINING REGULAR EXERCISE

The literature on this subject, including animal studies, implies that potential benefits accrue with long-term, regular exercise. The exercise parameters cannot be precisely defined, but the connotation is aerobic physical exercise that is sufficient to increase the heart rate and the need for oxygen. Presumably, this must be sustained (eg, for at least 20–30 minutes per session) and ongoing. Ultimately, this translates into what physiologists characterize as cardiovascular fitness,

EXERCISE MODALITIES

Although other medical conditions may limit the extent of exercise, modalities should be available for all people, except perhaps those with major cardiopulmonary disease or major organ failure. There is a wide variety of such aerobic exercise options, including walking, gym or health club routines, driveway basketball, and home activities, such as shoveling snow, raking leaves, or other yard work. Impaired ambulation does not preclude certain sitting exercises, such as use of rowing machines,

IMPROVEMENT IN COGNITIVE SCORES IN HEALTHY ADULTS

Recent meta-analyses of 29 randomized controlled trials (RCTs) documented significant cognitive benefits from sustained exercise in adults without dementia (although 3 of the 29 trials enrolled patients with MCI).10 Significantly improved scores were noted in memory, attention, processing speed, and executive function, albeit with only modest improvement. Because the benefits accrued during 1 to 12 months of exercise (except for one 18-month trial), these findings are less easily explained by

FUNCTIONAL MRI COGNITIVE NETWORKS IN HEALTHY SENIORS

Functional brain MRI (fMRI) during cognitive tasks has also documented significantly improved cognitive networks with exercise or fitness. In one 6-month RCT among seniors, aerobic exercise translated into significantly improved cortical connectivity and activation, compared with controls.11 In a 12-month RCT, aerobic exercise likewise improved cognitive fMRI network connectivity; however, the control group undergoing nonaerobic stretching and toning also had improved fMRI outcomes.12

In

MRI GRAY MATTER VOLUME LOSS IN SENIORS

Brain gray matter volumes decrease with advancing age, as routinely seen in the clinic with brain MRI. In contrast to neurodegenerative disorders, which are associated with neuronal loss, the reductions of gray matter volumes seen in normal aging primarily reflect loss of neuropil and synapses.4,5

A recent RCT in a large cohort of seniors documented significantly larger hippocampal volumes after 1 year of aerobic exercise, compared with the control intervention of simple stretching and toning.15

MIDLIFE EXERCISE AND REDUCED RISKS OF LATER DEMENTIA AND MCI

Adults who routinely engaged in physical activities, sports, or regular exercise in midlife carried a significantly lower risk of dementia years later, based on a recent meta-analysis of prospective cohort studies.23 Thus, reduction of dementia risk was documented in 10 of 11 studies, with an estimated relative risk of 0.72 (P<.001).23

Several prospective cohort investigations have reported significantly reduced subsequent risks of MCI associated with midlife exercise.24, 25, 26 A

INFLUENCE OF PHYSICAL ACTIVITY ON MORTALITY IN AD PATIENTS

A population-based, prospective cohort study of incident AD patients revealed that those with maintained physical activity had a significantly reduced risk of mortality.29 This was true even after statistically adjusting for APOE genotype, medical comorbidities, and cognitive performance. Again, however, reverse causality cannot be excluded.

SHORT-TERM COGNITIVE BENEFIT AMONG THOSE WITH MCI OR DEMENTIA

Reverse causality would not explain improved cognitive scores in short-term RCTs. A meta-analysis30 of RCTs in seniors with MCI or dementia tabulated outcomes with exercise durations spanning 2 to 112 weeks. Among the 12 trials, significant cognitive benefits were documented compared with control outcomes.

Several more recent studies have added to this literature. Most compelling was the Australian trial randomizing 170 subjects with “memory problems” to 6 months of moderate-intensity exercise

PLAUSIBILITY FROM ANIMAL STUDIES

The studies in humans suggest that exercise may improve cognition in the short term, reduce risks of dementia or MCI in the long term, and reduce the age-associated progressive loss of brain volume. This issue lends itself to assessment in animal models, in which it is also possible to study putative biological mechanisms.

EXERCISE IMPROVES COGNITION IN ANIMALS

Exercised rats or mice (eg, treadmills and running wheels) have significantly better scores on memory tests or object recognition compared with their more sedentary counterparts.36, 37, 38, 39, 40, 41, 42 Conversely, immobilization had the opposite effect, with reduced cognitive scores.43 These findings have been extended to primates; monkeys with scheduled exercise for 5 months had significantly better cognitive scores than sedentary animals.44

EVIDENCE FOR ENHANCED NEUROPLASTICITY INDUCED BY EXERCISE IN ANIMALS

Brain neuroplasticity is a fundamental mechanism for learning, memory, and general cognition. A voluminous literature in rats and mice has documented multiple mechanisms by which exercise may facilitate such neuroplasticity. Thus, exercise has been shown to increase expression of synaptic plasticity genes,45 gene products such as synapsin I and synaptophysin,46,47 and various neuroplasticity-related transcription factors such as cyclic adenosine monophosphate response element binding and

BRAIN EXPRESSION OF NEUROTROPHIC FACTORS INDUCED BY EXERCISE IN ANIMALS

Neurotrophic factors appear to be especially involved in learning and neuroplasticity. Brain-derived neurotrophic factor (BDNF) has been most extensively investigated and, in vitro, modulates brain plasticity, including increasing neuritic outgrowth and synaptic function. It also promotes in vitro survival of a vast array of neurons affected by neurodegenerative conditions, including AD.56 Numerous investigations in mice or rats have found elevated brain BDNF concentrations and expression with

EXERCISE AND HIPPOCAMPAL NEUROGENESIS IN HUMANS

The hippocampus is crucial for memory and progressively degenerates in patients with AD, an effect already apparent in the earliest stages of dementia (MCI).63 The hippocampal dentate gyrus is also the region most vulnerable to aging.64 However, this region is one of the few brain regions that supports neurogenesis, and dentate gyrus neurogenesis is significantly facilitated by exercise in animal studies, as previously mentioned.50, 52, 53, 54, 65

Regional hippocampal dentate gyrus blood volume

NEUROTROPHIC FACTORS, COGNITION, AND EXERCISE IN HUMANS

Theoretically, neurotrophic factors may be important in combating age-related brain atrophy and perhaps neurodegenerative disease. In contrast to laboratory animals, however, brain concentrations of neurotrophic factors cannot easily be studied in humans. Human investigations have focused on circulating levels, which may or may not reflect what is going on within the brain.

BDNF is widely expressed throughout the human adult brain,56 whereas levels are significantly reduced in the brains of AD

EXERCISE IMPACT ON BRAIN β-AMYLOID AND TAU PROTEIN

Alzheimer disease is the most common neurodegenerative dementia and is neuropathologically marked by the accumulation of neuritic plaques, as well as neurofibrillary tangles containing hyperphosphorylated tau protein. Perhaps a crucial inciting factor for AD development is the brain deposition of β-amyloid, the primary component of neuritic plaques. Brain accumulation of β-amyloid can be assessed in vivo using Pittsburgh compound B positron emission tomography. One recent investigation

ATTENUATION OF VASCULAR CONTRIBUTIONS TO NEURODEGENERATIVE DEMENTIA BY EXERCISE

There is a striking overlap of the risk factors for AD and vascular dementia. Glucose intolerance and diabetes mellitus, hypertension, hyperlipidemia, and obesity contribute to not only vascular dementia but also to the risk of neurodegenerative dementia.6 Intuitively, the influence of these vascular factors may be indirect via superimposed small vessel disease (eg, leukoaraiosis, lacunar strokes, and microbleeds). The added burden of cerebrovascular brain damage may simply superimpose on

OTHER BENEFICIAL EFFECTS OF EXERCISE

Numerous noncognitive, nonvascular benefits additionally benefit from exercise, which may be especially relevant to an aging population. This includes reduction of osteoporosis and fracture risk,118 age-related sarcopenia,119 and benefits directed at depression120 and anxiety.121 An exercise program may improve behavioral management in seniors with dementia122 and fall risk.123 Importantly, long-term physical activity and fitness reduce mortality risk in the general population.117,124

ADVERSE EFFECTS OF EXERCISE

Advocating for an intervention (in this case, exercise) should be balanced against possible adverse effects. Exercise may result in orthopedic injuries, increase fall risk, and provoke acute coronary syndromes. Thus, physicians should help patients select exercise programs compatible with their capabilities and cardiopulmonary status. In general, people who have been sedentary for an extended time should begin an exercise program with modest exercise targets, but escalating as fitness is

RESISTANCE TRAINING

Although the focus of this article has been on aerobic fitness, limited studies have suggested that regular resistance exercise (pushing or pulling against fixed weighting) may also improve cognition. Indeed, improved cognitive scores were documented in RCTs conducted for 2,125 6,101 and 12126 months. An additional 1-year follow-up in this last study revealed that cognitive benefits were sustained in the exercise group compared with the sedentary group.127 However, whole-brain volumes were

IS MORE EXERCISE BETTER?

The literature cited herein suggests cognitive benefits from aerobic exercise, but it remains unclear whether there are threshold effects or whether exercise duration and intensity are important variables. In mice, longer durations of exercise were more effective than shorter durations in attenuating the neuropathologic and clinical effects of the dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.128,129 In a single human study, serum BDNF levels increased with exercise in

AEROBIC EXERCISE PRESCRIPTION

Aerobic exercise implies training that elevates heart rate and increases Vo2, but the exercise parameters to recommend are not well delineated. The human trials summarized herein have primarily used moderate aerobic exercise, which typically implies exercise sufficient to elevate heart rate or Vo2 to approximately 60% of the maximum. For example, in 2 RCTs, the dose of 150 minutes of moderate aerobic exercise per week was sufficient to be cognitively protective31 and associated with increased

CONCLUSION

These data suggest that aerobic exercise is associated with a reduced risk of cognitive impairment and dementia; it may slow dementing illness. A compelling argument can be made for this via 2 plausible biologic pathways. First, a convergence of evidence from both animal and human studies suggests that aerobic exercise may attenuate progression of neurodegenerative processes and age-related loss of synapses and neuropil. This may occur via a direct influence on neurodegenerative disease

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    Dr Petersen reports the following relationships: Pfizer (Wyeth), Chair, Safety Monitoring Committee; Janssen Alzheimer's Immunotherapy (Elan), Chair, Safety Monitoring Committee; consultant for Elan Pharmaceuticals and GE Healthcare.

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