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

  • J. Eric Ahlskog
    Correspondence
    Individual reprints of this article are not available. Address correspondence to J. Eric Ahlskog, PhD, MD, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905
    Affiliations
    Department of Neurology, Mayo Clinic, Rochester, MN
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  • Yonas E. Geda
    Affiliations
    Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN

    Department of Health Sciences Research, Mayo Clinic, Rochester, MN
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  • Neill R. Graff-Radford
    Affiliations
    Department of Neurology, Mayo Clinic, Jacksonville, FL
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  • Author Footnotes
    1 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.
    Ronald C. Petersen
    Footnotes
    1 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.
    Affiliations
    Department of Neurology, Mayo Clinic, Rochester, MN

    Department of Health Sciences Research, Mayo Clinic, Rochester, MN
    Search for articles by this author
  • Author Footnotes
    1 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.
      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.
      AD (Alzheimer disease), BDNF (brain-derived neurotrophic factor), fMRI (functional brain magnetic resonance imaging), IGF-1 (insulinlike growth factor 1), MCI (mild cognitive impairment), MRI (magnetic resonance imaging), RCT (randomized controlled trial), Vo2 (oxygen consumption per unit time)
      Dementia is a major threat to our aging population.
      Besides destroying life quality of affected patients, it affects immediate family, turning spouses or children into caregivers and often straining family finances. Alzheimer disease (AD) accounts for most dementia cases,
      • Knopman DS
      • Boeve BF
      • Petersen RC
      Essentials of the proper diagnoses of mild cognitive impairment, dementia, and major subtypes of dementia.
      with contributions from dementia with Lewy bodies, vascular disease, frontotemporal degeneration syndromes, and various other less common disorders. Less devastating but also disrupting life quality is mild cognitive impairment (MCI), documented in more than 10% of seniors older than 70 years, with more than 20% affected after the age of 80 years.
      • Petersen RC
      • Roberts RO
      • Knopman DS
      • et al.
      Prevalence of mild cognitive impairment is higher in men: the Mayo Clinic Study of Aging.
      Often MCI is a prelude to subsequent dementia.
      • Petersen RC
      • Stevens JC
      • Ganguli M
      • Tangalos EG
      • Cummings JL
      • DeKosky ST
      Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.
      Notable also is the subtle loss of cognitive skills often accompanying normal aging. Seniors frequently experience reduced memory for names and telephone numbers. Whether the substrate is the progressive loss of gray matter routinely seen with brain magnetic resonance imaging (MRI) of seniors is debatable; indeed, normal brain aging is accompanied by loss of synaptic connections and attenuated neuropil.
      • Terry RD
      • Katzman R
      Life span and synapses: will there be a primary senile dementia?.
      • Hof PR
      • Morrison JH
      The aging brain: morphomolecular senescence of cortical circuits.
      The neurodegenerative dementias are presumed to be proteinopathies, characterized by aggregation of a specific protein within the brain, such as β-amyloid and microtubule-associated protein tau in AD or a-synuclein in dementia with Lewy bodies. Despite intensive research directed at these and other neurodegenerative diseases, no drug effectively targets the pathogenic substrates. No medication has been proven to reduce the subsequent risk of dementia or age-related cognitive impairment.

      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 and, moreover, cerebrovascular small vessel disease (eg, leukoaraiosis and lacunar disease) appears additive with neurodegenerative processes to cause dementia.
      • Knopman DS
      • Roberts R
      Vascular risk factors: imaging and neuropathology correlates.
      These atherosclerotic cerebrovascular mechanisms are distinctive from neurodegeneration and age-related loss of neuropil and synapses. Because the benefit of exercise on atherosclerotic (cerebrovascular) risk seems well established, this contribution to the subject will not be a focus of this article.
      Our focus is on the scientific basis for advocating regular exercise as a prophylactic and perhaps disease-slowing treatment of neurodegenerative and age-related dementia and MCI. Although certain studies in humans make it difficult to separate vascular contributions, the literature in the aggregate suggests that exercise may have more direct favorable effects on brain neuroplasticity and resilience to brain aging and neurodegeneration.
      A recent National Institutes of Health State-of-the-Science Statement took a nihilistic view of exercise as a disease-modifying influence on cognition or dementing illness.
      • Daviglus ML
      • Bell CC
      • Berrettini W
      • et al.
      NIH State-of-the-Science Conference Statement: preventing Alzheimer's disease and cognitive decline [published online ahead of print April 28, 2010].
      • Plassman BL
      • Williams Jr, JW
      • Burke JR
      • Holsinger T
      • Benjamin S
      Systematic review: factors associated with risk for and possible prevention of cognitive decline in later life.
      However, as pointed out in a subsequent critique of this statement, the conclusions were based on a narrow scope of data.
      • Flicker L
      • Liu-Ambrose T
      • Kramer AF
      Why so negative about preventing cognitive decline and dementia? The jury has already come to the verdict for physical activity and smoking cessation [editorial].
      We present evidence that argues for the benefit of exercise on cognition and the forestalling of later-life cognitive decline. In contrast to the recent National Institutes of Health consensus statement,
      • Daviglus ML
      • Bell CC
      • Berrettini W
      • et al.
      NIH State-of-the-Science Conference Statement: preventing Alzheimer's disease and cognitive decline [published online ahead of print April 28, 2010].
      • Plassman BL
      • Williams Jr, JW
      • Burke JR
      • Holsinger T
      • Benjamin S
      Systematic review: factors associated with risk for and possible prevention of cognitive decline in later life.
      we considered a broad expanse of both animal and human studies relevant to this topic. In an attempt to capture the relevant literature, we reviewed all publications identified by a PubMed search using the keyword cognition cross-referenced with exercise (identifying 1603 publications, without date limitations) and identified additional relevant articles via review of bibliographies from these and other publications.

      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, objectively assessed with measurement of oxygen uptake during peak exercise (such as on a treadmill); this is reported as peak oxygen consumption per unit time (Vo2), with higher values indicative of better fitness.
      Limited studies have also specifically addressed resistance exercise (effort against weighting or resistance) and cognition; however, this literature is currently insufficient to draw conclusions. Hence, we primarily focus on aerobic-type exercise that potentially leads to physical 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, exercise bicycles, or other gym 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).
      • Smith PJ
      • Blumenthal JA
      • Hoffman BM
      • et al.
      Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials.
      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 the secondary influence of exercise on cerebrovascular disease (eg, leukoaraiosis, lacune, or stroke risk).

      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.
      • Colcombe SJ
      • Kramer AF
      • Erickson KI
      • et al.
      Cardiovascular fitness, cortical plasticity, and aging.
      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.
      • Voss MW
      • Prakash RS
      • Erickson KI
      • et al.
      Plasticity of brain networks in a randomized intervention trial of exercise training in older adults.
      In cross-sectional analyses, physically fit seniors had fMRI evidence of significantly better cortical connectivity and activation during cognitive tasks than unfit seniors (assessed by peak Vo2 during exercise).
      • Colcombe SJ
      • Kramer AF
      • Erickson KI
      • et al.
      Cardiovascular fitness, cortical plasticity, and aging.
      • Voss MW
      • Erickson KI
      • Prakash RS
      • et al.
      Functional connectivity: a source of variance in the association between cardiorespiratory fitness and cognition?.
      Physically fit seniors also performed significantly better on cognitive tasks than unfit seniors in these cross-sectional studies.
      • Colcombe SJ
      • Kramer AF
      • Erickson KI
      • et al.
      Cardiovascular fitness, cortical plasticity, and aging.
      • Voss MW
      • Erickson KI
      • Prakash RS
      • et al.
      Functional connectivity: a source of variance in the association between cardiorespiratory fitness and cognition?.
      • Gordon BA
      • Rykhlevskaia EI
      • Brumback CR
      • et al.
      Neuroanatomical correlates of aging, cardiopulmonary fitness level, and education.

      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.
      • Terry RD
      • Katzman R
      Life span and synapses: will there be a primary senile dementia?.
      • Hof PR
      • Morrison JH
      The aging brain: morphomolecular senescence of cortical circuits.
      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.
      • Erickson KI
      • Voss MW
      • Prakash RS
      • et al.
      Exercise training increases size of hippocampus and improves memory.
      This finding was associated with significant improvement in the primary cognitive outcome measure of spatial memory. Similar exercise outcomes have been documented in the neocortex. Thus, two 6-month RCTs of aerobic exercise in seniors without dementia were associated with increased cortical volumes compared with sedentary interventions.
      • Colcombe SJ
      • Erickson KI
      • Scalf PE
      • et al.
      Aerobic exercise training increases brain volume in aging humans.
      • Ruscheweyh R
      • Willemer C
      • Kruger K
      • et al.
      Physical activity and memory functions: an interventional study.
      In a long-term, prospective cohort study, the usual weekly walking distances reported by healthy adults at baseline were positively associated with neocortical and hippocampal MRI volumes 9 years later.
      • Erickson KI
      • Raji CA
      • Lopez OL
      • et al.
      Physical activity predicts gray matter volume in late adulthood: the Cardiovascular Health Study.
      In a large, cross-sectional study of seniors without dementia, physical fitness, assessed by treadmill exercise testing (peak Vo2), was highly and significantly associated with hippocampal volumes on MRI (controlling for age, sex, and educational level).
      • Erickson KI
      • Prakash RS
      • Voss MW
      • et al.
      Aerobic fitness is associated with hippocampal volume in elderly humans.
      In other cross-sectional studies, physical fitness (measured by peak Vo2) was associated with better preservation of gray matter volumes among both cognitively normal seniors
      • Gordon BA
      • Rykhlevskaia EI
      • Brumback CR
      • et al.
      Neuroanatomical correlates of aging, cardiopulmonary fitness level, and education.
      • Colcombe SJ
      • Erickson KI
      • Raz N
      • et al.
      Aerobic fitness reduces brain tissue loss in aging humans.
      and patients with early AD.
      • Burns JM
      • Cronk BB
      • Anderson HS
      • et al.
      Cardiorespiratory fitness and brain atrophy in early Alzheimer disease.
      • Honea RA
      • Thomas GP
      • Harsha A
      • et al.
      Cardiorespiratory fitness and preserved medial temporal lobe volume in Alzheimer disease.
      The control groups in these latter 2 studies, however, did not generate expected results; in these seniors without dementia, there was no association of cardiorespiratory fitness (peak Vo2) with gray matter volumes.
      • Burns JM
      • Cronk BB
      • Anderson HS
      • et al.
      Cardiorespiratory fitness and brain atrophy in early Alzheimer disease.
      • Honea RA
      • Thomas GP
      • Harsha A
      • et al.
      Cardiorespiratory fitness and preserved medial temporal lobe volume in Alzheimer disease.

      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.
      • Hamer M
      • Chida Y
      Physical activity and risk of neurodegenerative disease: a systematic review of prospective evidence.
      Thus, reduction of dementia risk was documented in 10 of 11 studies, with an estimated relative risk of 0.72 (P<.001).
      • Hamer M
      • Chida Y
      Physical activity and risk of neurodegenerative disease: a systematic review of prospective evidence.
      Several prospective cohort investigations have reported significantly reduced subsequent risks of MCI associated with midlife exercise.
      • Laurin D
      • Verreault R
      • Lindsay J
      • MacPherson K
      • Rockwood K
      Physical activity and risk of cognitive impairment and dementia in elderly persons.
      • Singh-Manoux A
      • Hillsdon M
      • Brunner E
      • Marmot M
      Effects of physical activity on cognitive functioning in middle age: evidence from the Whitehall II Prospective Cohort Study.
      • Jedrziewski MK
      • Ewbank DC
      • Wang H
      • Trojanowski JQ
      Exercise and cognition: results from the National Long Term Care Survey.
      A population-based, case-control study similarly found that moderate exercise retrospectively reported for midlife was associated with a significantly reduced risk of MCI.
      • Geda YE
      • Roberts RO
      • Knopman DS
      • et al.
      Physical exercise, aging, and mild cognitive impairment: a population-based study.
      Reduction of MCI risk with retrospectively reported earlier life exercise was also documented in a cross-sectional study of a large female cohort.
      • Middleton LE
      • Barnes DE
      • Lui LY
      • Yaffe K
      Physical activity over the life course and its association with cognitive performance and impairment in old age.
      One caveat: the association of midlife exercise with later cognitive preservation could be explained by reverse causality. In other words, those with very early, preclinical neurodegenerative disease might be disinclined to exercise.

      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.
      • Scarmeas N
      • Luchsinger JA
      • Brickman AM
      • et al.
      Physical activity and Alzheimer disease course.
      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-analysis
      • Heyn P
      • Abreu BC
      • Ottenbacher KJ
      The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis.
      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 vs a sedentary routine.
      • Lautenschlager NT
      • Cox KL
      • Flicker L
      • et al.
      Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial.
      The exercise group had significantly better scores on the primary outcome measure after the 6 months, the Alzheimer Disease Assessment Scale-Cognitive Subscale; this benefit persisted at 12 and 18 months. Interestingly, they noted that the extent of improvement on the Alzheimer Disease Assessment Scale-Cognitive Subscale compared favorably to the effect of donepezil documented in another large clinical trial.
      • Petersen RC
      • Thomas RG
      • Grundman M
      • et al.
      Vitamin E and donepezil for the treatment of mild cognitive impairment.
      A similar outcome in seniors with MCI was documented in one smaller 6-month RCT of “high-intensity aerobic exercise” vs sedentary controls (stretching); however, the improvement was predominantly in women.
      • Baker LD
      • Frank LL
      • Foster-Schubert K
      • et al.
      Effects of aerobic exercise on mild cognitive impairment: a controlled trial.
      One additional RCT in seniors with MCI identified similar but not statistically significant trends after 1 year of exercise; the investigators commented that the analysis was compromised by suboptimal adherence to the exercise program.
      • van Uffelen JG
      • Chinapaw MJ
      • van Mechelen W
      • Hopman-Rock M
      Walking or vitamin B for cognition in older adults with mild cognitive impairment? A randomised controlled trial.
      In women with dementia, a small RCT of regular exercise for 1 year significantly improved the Mini-Mental State Examination score compared with slight (nonsignificant) worsening in the sedentary control group.
      • Kwak YS
      • Um SY
      • Son TG
      • Kim DJ
      Effect of regular exercise on senile dementia patients.
      Of note, 2 of these trials
      • Lautenschlager NT
      • Cox KL
      • Flicker L
      • et al.
      Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial.
      • van Uffelen JG
      • Chinapaw MJ
      • van Mechelen W
      • Hopman-Rock M
      Walking or vitamin B for cognition in older adults with mild cognitive impairment? A randomised controlled trial.
      were included in the meta-analysis by Smith et al.
      • Smith PJ
      • Blumenthal JA
      • Hoffman BM
      • et al.
      Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials.

      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.
      • Adlard PA
      • Perreau VM
      • Engesser-Cesar C
      • Cotman CW
      The time-course of induction of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus following voluntary exercise.
      • Vaynman S
      • Ying Z
      • Gomez-Pinilla F
      Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition.
      • van Praag H
      • Christie BR
      • Sejnowski TJ
      • Gage FH
      Running enhances neurogenesis, learning, and long-term potentiation in mice.
      • van Praag H
      • Shubert T
      • Zhao C
      • Gage FH
      Exercise enhances learning and hippocampal neurogenesis in aged mice.
      • Ding Q
      • Vaynman S
      • Akhavan M
      • Ying Z
      • Gomez-Pinilla F
      Insulin-like growth factor I interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate aspects of exercise-induced cognitive function.
      • O'Callaghan RM
      • Ohle R
      • Kelly AM
      The effects of forced exercise on hippocampal plasticity in the rat: a comparison of LTP, spatial- and non-spatial learning.
      • Berchtold NC
      • Castello N
      • Cotman CW
      Exercise and time-dependent benefits to learning and memory.
      Conversely, immobilization had the opposite effect, with reduced cognitive scores.
      • Yasuhara T
      • Hara K
      • Maki M
      • et al.
      Lack of exercise, via hindlimb suspension, impedes endogenous neurogenesis.
      These findings have been extended to primates; monkeys with scheduled exercise for 5 months had significantly better cognitive scores than sedentary animals.
      • Rhyu IJ
      • Bytheway JA
      • Kohler SJ
      • et al.
      Effects of aerobic exercise training on cognitive function and cortical vascularity in monkeys.

      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,
      • Stranahan AM
      • Lee K
      • Becker KG
      • et al.
      Hippocampal gene expression patterns underlying the enhancement of memory by running in aged mice.
      gene products such as synapsin I and synaptophysin,
      • Vaynman S
      • Ying Z
      • Gomez-Pinilla F
      Exercise induces BDNF and synapsin I to specific hippocampal subfields.
      • Vaynman SS
      • Ying Z
      • Yin D
      • Gomez-Pinilla F
      Exercise differentially regulates synaptic proteins associated to the function of BDNF.
      and various neuroplasticity-related transcription factors such as cyclic adenosine monophosphate response element binding and intracellular kinases.
      • Berchtold NC
      • Castello N
      • Cotman CW
      Exercise and time-dependent benefits to learning and memory.
      • Shen H
      • Tong L
      • Balazs R
      • Cotman CW
      Physical activity elicits sustained activation of the cyclic AMP response element-binding protein and mitogen-activated protein kinase in the rat hippocampus.
      • Gomez-Pinilla F
      • Vaynman S
      • Ying Z
      Brain-derived neurotrophic factor functions as a metabotrophin to mediate the effects of exercise on cognition.
      Hippocampal dendritic length and dendritic spine complexity are enhanced with exercise.
      • Eadie BD
      • Redila VA
      • Christie BR
      Voluntary exercise alters the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dendritic complexity, and spine density.
      • Redila VA
      • Christie BR
      Exercise-induced changes in dendritic structure and complexity in the adult hippocampal dentate gyrus.
      Neurogenesis within the hippocampal dentate gyrus is also induced by exercise.
      • Eadie BD
      • Redila VA
      • Christie BR
      Voluntary exercise alters the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dendritic complexity, and spine density.
      • Trejo JL
      • Carro E
      • Torres-Aleman I
      Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus.
      • Fabel K
      • Fabel K
      • Tam B
      • et al.
      VEGF is necessary for exercise-induced adult hippocampal neurogenesis.
      • Farmer J
      • Zhao X
      • van Praag H
      • Wodtke K
      • Gage FH
      • Christie BR
      Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo.
      Finally, long-term potentiation, which is thought to be a primary neurophysiologic substrate in learning, is potentiated by exercise,
      • van Praag H
      • Christie BR
      • Sejnowski TJ
      • Gage FH
      Running enhances neurogenesis, learning, and long-term potentiation in mice.
      • O'Callaghan RM
      • Ohle R
      • Kelly AM
      The effects of forced exercise on hippocampal plasticity in the rat: a comparison of LTP, spatial- and non-spatial learning.
      • Farmer J
      • Zhao X
      • van Praag H
      • Wodtke K
      • Gage FH
      • Christie BR
      Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo.
      although this effect was confined to male animals in one study.
      • Titterness AK
      • Wiebe E
      • Kwasnica A
      • Keyes G
      • Christie BR
      Voluntary exercise does not enhance long-term potentiation in the adolescent female dentate gyrus.

      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.
      • Murer MG
      • Yan Q
      • Raisman-Vozari R
      Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease.
      Numerous investigations in mice or rats have found elevated brain BDNF concentrations and expression with exercise,
      • Adlard PA
      • Perreau VM
      • Engesser-Cesar C
      • Cotman CW
      The time-course of induction of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus following voluntary exercise.
      • Vaynman S
      • Ying Z
      • Gomez-Pinilla F
      Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition.
      • O'Callaghan RM
      • Ohle R
      • Kelly AM
      The effects of forced exercise on hippocampal plasticity in the rat: a comparison of LTP, spatial- and non-spatial learning.
      • Berchtold NC
      • Castello N
      • Cotman CW
      Exercise and time-dependent benefits to learning and memory.
      • Vaynman S
      • Ying Z
      • Gomez-Pinilla F
      Exercise induces BDNF and synapsin I to specific hippocampal subfields.
      • Vaynman SS
      • Ying Z
      • Yin D
      • Gomez-Pinilla F
      Exercise differentially regulates synaptic proteins associated to the function of BDNF.
      • Gomez-Pinilla F
      • Vaynman S
      • Ying Z
      Brain-derived neurotrophic factor functions as a metabotrophin to mediate the effects of exercise on cognition.
      • Farmer J
      • Zhao X
      • van Praag H
      • Wodtke K
      • Gage FH
      • Christie BR
      Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo.
      • Neeper SA
      • Gomez-Pinilla F
      • Choi J
      • Cotman CW
      Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain.
      • Berchtold NC
      • Chinn G
      • Chou M
      • Kesslak JP
      • Cotman CW
      Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus.
      • Tajiri N
      • Yasuhara T
      • Shingo T
      • et al.
      Exercise exerts neuroprotective effects on Parkinson's disease model of rats.
      • Wu SY
      • Wang TF
      • Yu L
      • et al.
      Running exercise protects the substantia nigra dopaminergic neurons against inflammation-induced degeneration via the activation of BDNF signaling pathway.
      although with one exception.
      • Titterness AK
      • Wiebe E
      • Kwasnica A
      • Keyes G
      • Christie BR
      Voluntary exercise does not enhance long-term potentiation in the adolescent female dentate gyrus.
      Insulin-like growth factor 1 (IGF-1) interacts with BDNF and is likewise elevated in the rat brain by exercise.
      • Ding Q
      • Vaynman S
      • Akhavan M
      • Ying Z
      • Gomez-Pinilla F
      Insulin-like growth factor I interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate aspects of exercise-induced cognitive function.
      • Carro E
      • Nunez A
      • Busiguina S
      • Torres-Aleman I
      Circulating insulinlike growth factor I mediates effects of exercise on the brain.
      Rat brain concentrations of glial-derived neurotrophic factor are similarly upregulated by exercise.
      • Tajiri N
      • Yasuhara T
      • Shingo T
      • et al.
      Exercise exerts neuroprotective effects on Parkinson's disease model of rats.
      • Cohen AD
      • Tillerson JL
      • Smith AD
      • Schallert T
      • Zigmond MJ
      Neuroprotective effects of prior limb use in 6-hydroxydopamine-treated rats: possible role of GDNF.

      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).
      • Morra JH
      • Tu Z
      • Apostolova LG
      • et al.
      Automated mapping of hippocampal atrophy in 1-year repeat MRI data from 490 subjects with Alzheimer's disease, mild cognitive impairment, and elderly controls.
      The hippocampal dentate gyrus is also the region most vulnerable to aging.
      • Small SA
      • Chawla MK
      • Buonocore M
      • Rapp PR
      • Barnes CA
      Imaging correlates of brain function in monkeys and rats isolates a hippocampal subregion differentially vulnerable to aging.
      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.
      • Eadie BD
      • Redila VA
      • Christie BR
      Voluntary exercise alters the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dendritic complexity, and spine density.
      • Trejo JL
      • Carro E
      • Torres-Aleman I
      Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus.
      • Fabel K
      • Fabel K
      • Tam B
      • et al.
      VEGF is necessary for exercise-induced adult hippocampal neurogenesis.
      • Farmer J
      • Zhao X
      • van Praag H
      • Wodtke K
      • Gage FH
      • Christie BR
      Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo.
      • Pereira AC
      • Huddleston DE
      • Brickman AM
      • et al.
      An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus.
      Regional hippocampal dentate gyrus blood volume can be measured with brain MRI, and this was shown to be a neurogenesis biomarker in mice.
      • Pereira AC
      • Huddleston DE
      • Brickman AM
      • et al.
      An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus.
      Extending this to humans in a small, prospective, uncontrolled trial of young adults, 3 months of aerobic exercise resulted in significantly increased hippocampal dentate gyrus blood volume over baseline; other hippocampal regions were unchanged.
      • Pereira AC
      • Huddleston DE
      • Brickman AM
      • et al.
      An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus.
      This was interpreted as reflective of dentate gyrus angiogenesis and hence neurogenesis. It was associated with mildly improved cognitive scores. Fitness, as measured by peak Vo2, significantly correlated with individual differences in dentate gyrus blood volume.
      • Pereira AC
      • Huddleston DE
      • Brickman AM
      • et al.
      An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus.

      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,
      • Murer MG
      • Yan Q
      • Raisman-Vozari R
      Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease.
      whereas levels are significantly reduced in the brains of AD patients.
      • Phillips HS
      • Hains JM
      • Armanini M
      • Laramee GR
      • Johnson SA
      • Winslow JW
      BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease.
      • Connor B
      • Young D
      • Yan Q
      • Faull RL
      • Synek B
      • Dragunow M
      Brain-derived neurotrophic factor is reduced in Alzheimer's disease.
      • Holsinger RMD
      • Schnarr J
      • Henry P
      • Castelo VT
      • Fahnestock M
      Quantitation of BDNF mRNA in human parietal cortex by competitive reverse transcription-polymerase chain reaction: decreased levels in Alzheimer's disease.
      • Peng S
      • Wuu J
      • Mufson EJ
      • Fahnestock M
      Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer's disease.
      BDNF is rapidly transported in both directions across the blood-brain barrier,
      • Poduslo JF
      • Curran GL
      Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF.
      • Pan W
      • Banks WA
      • Fasold MB
      • Bluth J
      • Kastin AJ
      Transport of brain-derived neurotrophic factor across the blood-brain barrier.
      and hence measurement of circulating levels could be relevant to the brain. Thus, circulating BDNF levels are reduced in patients with AD
      • Yasutake C
      • Kuroda K
      • Yanagawa T
      • Okamura T
      • Yoneda H
      Serum BDNF, TNF-α and IL-Î2 levels in dementia patients.
      • Laske C
      • Stransky E
      • Leyhe T
      • et al.
      BDNF serum and CSF concentrations in Alzheimer's disease, normal pressure hydrocephalus and healthy controls.
      ; moreover, AD patients whose condition is rapidly declining have significantly lower serum BDNF concentrations than those whose condition is slowly declining.
      • Laske C
      • Stellos K
      • Hoffmann N
      • et al.
      Higher BDNF serum levels predict slower cognitive decline in Alzheimer's disease patients.
      Note also that in healthy young adults, BDNF appears to be released from the human brain by both short-term vigorous exercise
      • Rasmussen P
      • Brassard P
      • Adser H
      • et al.
      Evidence for a release of brain-derived neurotrophic factor from the brain during exercise.
      and long-term endurance training
      • Seifert T
      • Brassard P
      • Wissenberg M
      • et al.
      Endurance training enhances BDNF release from the human brain.
      on the basis of arterial and venous measurements.
      In cross-sectional studies of seniors, circulating BDNF levels have been significantly associated with cognitive test scores after adjusting for multiple covariables,
      • Komulainen P
      • Pedersen M
      • Hanninen T
      • et al.
      BDNF is a novel marker of cognitive function in ageing women: the DR's EXTRA Study.

      Swardfager W, Herrmann N, Marzolini S, et al. Brain derived neurotrophic factor, cardiopulmonary fitness and cognition in patients with coronary artery disease [published online ahead of print April 30, 2011]. Brain Behav Immun. doi:10.1016/j.bbi.2011.04.017.

      although confined to women in one study.
      • Komulainen P
      • Pedersen M
      • Hanninen T
      • et al.
      BDNF is a novel marker of cognitive function in ageing women: the DR's EXTRA Study.
      In fact, fitness (peak Vo2) was significantly correlated with both BDNF and cognitive improvement in one of these studies.

      Swardfager W, Herrmann N, Marzolini S, et al. Brain derived neurotrophic factor, cardiopulmonary fitness and cognition in patients with coronary artery disease [published online ahead of print April 30, 2011]. Brain Behav Immun. doi:10.1016/j.bbi.2011.04.017.

      Moreover, in a 1-year RCT of exercise among seniors, increased serum BDNF level was associated with increased hippocampal volume.
      • Knopman DS
      • Roberts R
      Vascular risk factors: imaging and neuropathology correlates.
      The study of aerobic exercise on plasma or serum BDNF levels has generated complex findings. Most investigations in young adults have documented significant transient increases of circulating BDNF with short-term aerobic exercise,
      • Gold SM
      • Schulz KH
      • Hartmann S
      • et al.
      Basal serum levels and reactivity of nerve growth factor and brain-derived neurotrophic factor to standardized acute exercise in multiple sclerosis and controls.
      • Ferris LT
      • Williams JS
      • Shen CL
      The effect of acute exercise on serum brain-derived neurotrophic factor levels and cognitive function.
      • Tang SW
      • Chu E
      • Hui T
      • Helmeste D
      • Law C
      Influence of exercise on serum brain-derived neurotrophic factor concentrations in healthy human subjects.
      • Rojas Vega S
      • Struder HK
      • Vera Wahrmann B
      • Schmidt A
      • Bloch W
      • Hollmann W
      Acute BDNF and cortisol response to low intensity exercise and following ramp incremental exercise to exhaustion in humans.
      with one exception.
      • Castellano V
      • White LJ
      Serum brain-derived neurotrophic factor response to aerobic exercise in multiple sclerosis.
      Prospective studies of long-term aerobic exercise, however, have generated negative or inconsistent results. Thus, 5 weeks of chronic aerobic exercise in young adults was associated with increased levels of circulating BDNF in one uncontrolled trial,
      • Zoladz JA
      • Pilc A
      • Majerczak J
      • Grandys M
      • Zapart-Bukowska J
      • Duda K
      Endurance training increases plasma brain-derived neurotrophic factor concentration in young healthy men.
      whereas two trials were negative (8–12 weeks; one controlled).
      • Castellano V
      • White LJ
      Serum brain-derived neurotrophic factor response to aerobic exercise in multiple sclerosis.
      • Schiffer T
      • Schulte S
      • Hollmann W
      • Bloch W
      • Struder HK
      Effects of strength and endurance training on brain-derived neurotrophic factor and insulin-like growth factor 1 in humans.
      In one RCT of patients with MCI, 6 months of “high-intensity aerobic exercise” resulted in a nonsignificant trend toward increased plasma BDNF levels in men but reduced in women (compared with control values).
      • Baker LD
      • Frank LL
      • Foster-Schubert K
      • et al.
      Effects of aerobic exercise on mild cognitive impairment: a controlled trial.
      Somewhat paradoxically, 2 cross-sectional studies documented an inverse relationship between physical fitness and serum BDNF concentrations.
      • Nofuji Y
      • Suwa M
      • Moriyama Y
      • et al.
      Decreased serum brain-derived neurotrophic factor in trained men.
      • Currie J
      • Ramsbottom R
      • Ludlow H
      • Nevill A
      • Gilder M
      Cardiorespiratory fitness, habitual physical activity and serum brain derived neurotrophic factor (BDNF) in men and women.
      The few prospective trials of resistance (not aerobic) exercise influences on plasma or serum BDNF levels have generated primarily negative results. In contrast to aerobic exercise, strength and resistance exercise did not elevate circulating BDNF concentrations.
      • Rojas Vega S
      • Knicker A
      • Hollmann W
      • Bloch W
      • Struder HK
      Effect of resistance exercise on serum levels of growth factors in humans.
      • Correia PR
      • Pansani A
      • Machado F
      • et al.
      Acute strength exercise and the involvement of small or large muscle mass on plasma brain-derived neurotrophic factor levels.
      • Goekint M
      • De Pauw K
      • Roelands B
      • et al.
      Strength training does not influence serum brain-derived neurotrophic factor.
      A prospective, controlled trial of strength training (10 weeks) failed to increase serum BDNF levels.
      • Goekint M
      • De Pauw K
      • Roelands B
      • et al.
      Strength training does not influence serum brain-derived neurotrophic factor.
      As an exception, 5 weeks of resistance exercise raised serum BDNF levels in one other prospective, uncontrolled trial in young men.
      • Yarrow JF
      • White LJ
      • McCoy SC
      • Borst SE
      Training augments resistance exercise induced elevation of circulating brain derived neurotrophic factor (BDNF).
      Insulin-like growth factor 1 is widely expressed in the human brain, and IGF-1 insufficiency has been proposed as a risk factor for AD.
      • Torres-Aleman I
      Mouse models of Alzheimer's dementia: current concepts and new trends.
      Patients with AD had significantly lower circulating IGF-1 levels than controls in one small cross-sectional study, and these levels were inversely correlated with the degree of cognitive impairment.
      • Murialdo G
      • Barreca A
      • Nobili F
      • et al.
      Relationships between cortisol, dehydroepiandrosterone sulphate and insulin-like growth factor-I system in dementia.
      Meta-analysis of the predominantly cross-sectional studies assessing circulating IGF-1 levels and cognition in seniors revealed a highly significant positive association.
      • Arwert LI
      • Deijen JB
      • Drent ML
      The relation between insulin-like growth factor I levels and cognition in healthy elderly: a meta-analysis.
      In healthy young adults, circulating IGF-1 is increased by exercise in most
      • Rojas Vega S
      • Knicker A
      • Hollmann W
      • Bloch W
      • Struder HK
      Effect of resistance exercise on serum levels of growth factors in humans.
      • Bang P
      • Brandt J
      • Degerblad M
      • et al.
      Exercise-induced changes in insulin-like growth factors and their low molecular weight binding protein in healthy subjects and patients with growth hormone deficiency.
      • Schwarz AJ
      • Brasel JA
      • Hintz RL
      • Mohan S
      • Cooper DM
      Acute effect of brief low- and high-intensity exercise on circulating insulin-like growth factor (IGF) I, II, and IGF-binding protein-3 and its proteolysis in young healthy men.
      • Copeland JL
      • Heggie L
      IGF-I and IGFBP-3 during continuous and interval exercise.
      but not all studies.
      • Stokes KA
      • Sykes D
      • Gilbert KL
      • Chen JW
      • Frystyk J
      Brief, high intensity exercise alters serum ghrelin and growth hormone concentrations but not IGF-I, IGF-II or IGF-I bioactivity.
      In young adults, long-term aerobic exercise failed to elevate circulating IGF-1 levels in 2 RCTs (12–16 weeks).
      • Schiffer T
      • Schulte S
      • Hollmann W
      • Bloch W
      • Struder HK
      Effects of strength and endurance training on brain-derived neurotrophic factor and insulin-like growth factor 1 in humans.
      • Arikawa AY
      • Kurzer MS
      • Thomas W
      • Schmitz KH
      No effect of exercise on insulin-like growth factor-I, insulin, and glucose in young women participating in a 16-week randomized controlled trial.
      In contrast to aerobic exercise, long-term resistance training elevated serum IGF-1 concentrations in 2 prospective, controlled trials
      • Borst SE
      • De Hoyos DV
      • Garzarella L
      • et al.
      Effects of resistance training on insulin-like growth factor-I and IGF binding proteins.
      • Cassilhas RC
      • Viana VA
      • Grassmann V
      • et al.
      The impact of resistance exercise on the cognitive function of the elderly.
      but not in another.
      • Borst SE
      • Vincent KR
      • Lowenthal DT
      • Braith RW
      Effects of resistance training on insulin-like growth factor and its binding proteins in men and women aged 60 to 85.

      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 (cross-sectional design) documented an inverse relationship between long-term exercise levels and brain Pittsburgh compound B imaging density in a large cohort of cognitively normal seniors.
      • Liang KY
      • Mintun MA
      • Fagan AM
      • et al.
      Exercise and Alzheimer's disease biomarkers in cognitively normal older adults.
      These brain imaging findings were mirrored by spinal fluid tau protein and β-amyloid42 biomarkers. Again, however, reverse causality cannot be excluded. A small RCT of 6 months of exercise in patients with MCI documented a nonsignificant trend toward reduced plasma concentrations of β-amyloid42 compared with sedentary controls.
      • Baker LD
      • Frank LL
      • Foster-Schubert K
      • et al.
      Effects of aerobic exercise on mild cognitive impairment: a controlled trial.
      Most investigations of exercise and brain β-amyloid deposition, however, have been performed using transgenic mice overexpressing pathogenic amyloid precursor protein (or presenilin 2
      • Um HS
      • Kang EB
      • Koo JH
      • et al.
      Treadmill exercise represses neuronal cell death in an aged transgenic mouse model of Alzheimer's disease.
      ). The findings have been mixed, with a reduction of brain pathogenic β-amyloid deposition or amyloid plaques in most
      • Um HS
      • Kang EB
      • Koo JH
      • et al.
      Treadmill exercise represses neuronal cell death in an aged transgenic mouse model of Alzheimer's disease.
      • Adlard PA
      • Perreau VM
      • Pop V
      • Cotman CW
      Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease.
      • Nichol KE
      • Poon WW
      • Parachikova AI
      • Cribbs DH
      • Glabe CG
      • Cotman CW
      Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid.
      • Um HS
      • Kang EB
      • Leem YH
      • et al.
      Exercise training acts as a therapeutic strategy for reduction of the pathogenic phenotypes for Alzheimer's disease in an NSE/APPsw-transgenic model.
      • Yuede CM
      • Zimmerman SD
      • Dong H
      • et al.
      Effects of voluntary and forced exercise on plaque deposition, hippocampal volume, and behavior in the Tg2576 mouse model of Alzheimer's disease.
      • Mirochnic S
      • Wolf S
      • Staufenbiel M
      • Kempermann G
      Age effects on the regulation of adult hippocampal neurogenesis by physical activity and environmental enrichment in the APP23 mouse model of Alzheimer disease.
      but not all studies.
      • Wolf SA
      • Kronenberg G
      • Lehmann K
      • et al.
      Cognitive and physical activity differently modulate disease progression in the amyloid precursor protein (APP)-23 model of Alzheimer's disease.
      • Parachikova A
      • Nichol KE
      • Cotman CW
      Short-term exercise in aged Tg2576 mice alters neuroinflammation and improves cognition.
      • Richter H
      • Ambree O
      • Lewejohann L
      • et al.
      Wheel-running in a transgenic mouse model of Alzheimer's disease: protection or symptom?.
      Neurofibrillary tangles are marked by hyperphosphorylated tau protein and are one of the pathological hallmarks of AD. In transgenic mice expressing a human pathogenic tau gene, 9 months of exercise prevented both the development of hippocampal tau disease and memory impairment, which were present in the sedentary control group.
      • Belarbi K
      • Burnouf S
      • Fernandez-Gomez FJ
      • et al.
      Beneficial effects of exercise in a transgenic mouse model of Alzheimer's disease-like Tau pathology.
      In 2 other studies, 12 weeks of exercise significantly reduced tau phosphorylation in transgenic mice expressing pathogenic tau
      • Leem YH
      • Lim HJ
      • Shim SB
      • Cho JY
      • Kim BS
      • Han PL
      Repression of tau hyperphosphorylation by chronic endurance exercise in aged transgenic mouse model of tauopathies.
      or presenilin 2
      • Um HS
      • Kang EB
      • Koo JH
      • et al.
      Treadmill exercise represses neuronal cell death in an aged transgenic mouse model of Alzheimer's disease.
      genes (compared with sedentary controls).

      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.
      • Knopman DS
      • Roberts R
      Vascular risk factors: imaging and neuropathology correlates.
      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 neurodegeneration. However, a more direct effect of these vascular risk factors on neurodegenerative processes is plausible. Regardless, long-term exercise is well known to attenuate each of these risk factors.
      • Smith JK
      Exercise and atherogenesis.
      • Pitsavos C
      • Panagiotakos D
      • Weinem M
      • Stefanadis C
      Diet, exercise and the metabolic syndrome.
      • Kokkinos P
      • Sheriff H
      • Kheirbek R
      Physical inactivity and mortality risk.

      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,
      • Rizzoli R
      • Bruyere O
      • Cannata-Andia JB
      • et al.
      Management of osteoporosis in the elderly.
      age-related sarcopenia,
      • Thomas DR
      Sarcopenia.
      and benefits directed at depression
      • Conn VS
      Depressive symptom outcomes of physical activity interventions: meta-analysis findings.
      and anxiety.
      • Dunn AL
      Review: exercise programmes reduce anxiety symptoms in sedentary patients with chronic illnesses.
      An exercise program may improve behavioral management in seniors with dementia
      • Teri L
      • Gibbons LE
      • McCurry SM
      • et al.
      Exercise plus behavioral management in patients with Alzheimer disease: a randomized controlled trial.
      and fall risk.
      • Allan LM
      • Ballard CG
      • Rowan EN
      • Kenny RA
      Incidence and prediction of falls in dementia: a prospective study in older people.
      Importantly, long-term physical activity and fitness reduce mortality risk in the general population.
      • Kokkinos P
      • Sheriff H
      • Kheirbek R
      Physical inactivity and mortality risk.
      • Lee DC
      • Artero EG
      • Sui X
      • Blair SN
      Mortality trends in the general population: the importance of cardiorespiratory fitness.

      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 progressively achieved.

      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,
      • Perrig-Chiello P
      • Perrig WJ
      • Ehrsam R
      • Staehelin HB
      • Krings F
      The effects of resistance training on well-being and memory in elderly volunteers.
      6,
      • Cassilhas RC
      • Viana VA
      • Grassmann V
      • et al.
      The impact of resistance exercise on the cognitive function of the elderly.
      and 12
      • Liu-Ambrose T
      • Nagamatsu LS
      • Graf P
      • Beattie BL
      • Ashe MC
      • Handy TC
      Resistance training and executive functions: a 12-month randomized controlled trial.
      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.
      • Davis JC
      • Marra CA
      • Beattie BL
      • et al.
      Sustained cognitive and economic benefits of resistance training among community-dwelling senior women: a 1-year follow-up study of the Brain Power study.
      However, whole-brain volumes were inexplicably reduced in this 12-month resistance training trial
      • Liu-Ambrose T
      • Nagamatsu LS
      • Graf P
      • Beattie BL
      • Ashe MC
      • Handy TC
      Resistance training and executive functions: a 12-month randomized controlled trial.
      ; this is in contrast to previously cited aerobic exercise trials in which cortical and hippocampal volumes were increased.
      • Erickson KI
      • Voss MW
      • Prakash RS
      • et al.
      Exercise training increases size of hippocampus and improves memory.
      • Colcombe SJ
      • Erickson KI
      • Scalf PE
      • et al.
      Aerobic exercise training increases brain volume in aging humans.
      • Ruscheweyh R
      • Willemer C
      • Kruger K
      • et al.
      Physical activity and memory functions: an interventional study.
      • Erickson KI
      • Raji CA
      • Lopez OL
      • et al.
      Physical activity predicts gray matter volume in late adulthood: the Cardiovascular Health Study.
      • Erickson KI
      • Prakash RS
      • Voss MW
      • et al.
      Aerobic fitness is associated with hippocampal volume in elderly humans.
      Obviously, resistance training may contribute to aerobic fitness if the focus is on lighter weights (lesser resistance), more repetitions, and brief rest periods. However, the effect of resistance training on cognition has been inadequately studied to date and is difficult to assess in animal studies.

      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.
      • Ahmad SO
      • Park JH
      • Stenho-Bittel L
      • Lau YS
      Effects of endurance exercise on ventral tegmental area neurons in the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid-treated mice.
      • Gerecke KM
      • Jiao Y
      • Pani A
      • Pagala V
      • Smeyne RJ
      Exercise protects against MPTP-induced neurotoxicity in mice.
      In a single human study, serum BDNF levels increased with exercise in proportion to the degree of lactate elevation.
      • Ferris LT
      • Williams JS
      • Shen CL
      The effect of acute exercise on serum brain-derived neurotrophic factor levels and cognitive function.
      Human clinical trials assessing exercise duration or intensity, however, have been confined to resistance training. In a 6-month RCT in seniors, 2 intensities of resistance exercises (moderate and high) resulted in similar degrees of cognitive benefit.
      • Cassilhas RC
      • Viana VA
      • Grassmann V
      • et al.
      The impact of resistance exercise on the cognitive function of the elderly.
      In another RCT, once-weekly resistance exercise significantly improved cognitive scores similar to twice-weekly exercise.
      • Liu-Ambrose T
      • Nagamatsu LS
      • Graf P
      • Beattie BL
      • Ashe MC
      • Handy TC
      Resistance training and executive functions: a 12-month randomized controlled trial.
      However, duration was important in this latter trial in that the cognitive benefit was only documented at 12 but not 6 months. These 2 trials, however, assessed resistance training, not aerobic exercise, per se.

      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 protective
      • Lautenschlager NT
      • Cox KL
      • Flicker L
      • et al.
      Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial.
      and associated with increased hippocampal volume plus improved spatial memory.
      • Erickson KI
      • Voss MW
      • Prakash RS
      • et al.
      Exercise training increases size of hippocampus and improves memory.
      Such moderate intensity is a practical exercise target, recognizing that greater exercise intensity might not be tolerated and lead to greater numbers of study dropouts or nonadherence, at least initially.
      Regular aerobic exercise gradually increased to achieve 60% of maximal heart rate or Vo2 and performed at least 150 minutes weekly seems reasonable as an initial regimen. This is similar to the recommendation of the American Heart Association, which advises “…moderate-intensity aerobic physical activity for a minimum of 30 minutes on five days each week or vigorous-intensity aerobic activity for a minimum of 20 minutes on three days each week”; parenthetically, they also recommended resistance exercises “for a minimum of two days each week.”
      • Nelson ME
      • Rejeski WJ
      • Blair SN
      • et al.
      Physical activity and public health in older adults: recommendation from the American College of Sports Medicine and the American Heart Association.
      Future research should investigate exercise parameters to better determine the optimal recommendations for preservation of cognition and brain health.
      Choice of exercise routines needs to be guided by patients' capabilities. Those with imbalance or lower limb arthritis may take advantage of health facilities that provide exercise machines used in the sitting position. The choice of exercise should also be consonant with patient interests because if too onerous it is likely to be abandoned. For very sedentary individuals, a therapist or knowledgeable trainer may be advisable to gradually introduce and escalate exercise routines and further reinforce patient effort.

      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 mechanisms or facilitation of neuroprotective neurotrophic factors and neuroplasticity. Not to be overlooked, however, is a second pathway, cerebrovascular disease. Cerebrovascular burden contributes to dementia risk, especially via small vessel disease (eg, lacunes and leukoaraiosis). Vascular risk factors are well known to be reduced by aerobic exercise. Thus, ongoing, moderate-intensity physical exercise should be considered as a prescription for lowering cognitive risks and slowing cognitive decline across the age spectrum.

      Author Interview

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