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How Long-term Aerobic Exercise Improves Brain Health

Dean Pomerleau

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We've known for quite some time that exercise (and CR!) can help stave off the cognitive decline that is often associated with aging. Scientists are now beginning to understand the mechanism underlying this effect.


Here is a popular press description:




of a new paper [1] that helps elucidate the physiological mechanism of brain health preservation via exercise.


The authors experimented with mice. They found that with age the support cells in the brain (microglia, astrocytes, etc.) are lost or become dysfunctional, reducing blood flow to neurons, increasing inflammation, etc. This age-related decline and damage was prevented in the mice that exercised (~2 miles per day on a running wheel). But exercise didn't have any positive effect in mice that were completely APOE-deficient.


It is interesting that the APOE gene is involved in the beneficial cognitive benefits of exercise, since variants in this gene (i.e. APOE4) are well known to be associated with increased risk of Alzheimer's disease.


Exactly what this means for people with APOE gene variants like APOE4 isn't clear, at least to me. Would exercise be somewhat of a waste of time for these people, unable to preserve cognitive health, like in the APOE-deficient mice? Or would exercise be more important for APOE4 carriers, to get the most from their relatively-impaired APOE activity on the brain?





[1] PLOS Biology, October 29, 2015; DOI: 10.1371/journal.pbio.1002279 (open access)


APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction.


Ileana Soto, Leah C. Graham, Hannah J. Richter, Stephen N. Simeone, Jake E. Radell, Weronika Grabowska, W. Keith Funkhouser, Megan C. Howell, Gareth R. Howell.




Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes. Importantly, long-term aerobic exercise from midlife to old age prevented this age-related neurovascular decline, reduced C1QA+ microglia/monocytes, and increased synaptic plasticity and overall behavioral capabilities of aged mice. Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise. Given the role of APOE in maintaining the neurovascular unit and as an anti-inflammatory molecule, this suggests a possible link between astrocytic Apoe, age-related neurovascular dysfunction and microglia/monocyte activation. To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE. Collectively, our data shows that neurovascular structures decline with age, a process that we propose to be intimately linked to complement activation in microglia/monocytes. Exercise prevents these changes, but not in the absence of APOE, opening up new avenues for understanding the complex interactions between neurovascular and neuroinflammatory responses in aging and neurodegenerative diseases such as Alzheimer’s disease.


Author Summary


Aging is frequently accompanied with frailty and cognitive decline. In recent years, increasing evidence has linked physical inactivity with the development of dementias such as Alzheimer’s disease. In fact, it is recognized that exercise combats frailty and cognitive decline in older adults, but the biological mechanisms involved are not completely known. Understanding the biological changes that trigger cognitive deterioration during aging and the mechanisms by which exercise improves health and brain function is key to ensuring the quality of life of the elderly population and to reducing risk of dementias such as Alzheimer’s disease. Here, we show that the cerebrovascular system in mice significantly deteriorates with age, and the structure and function of the blood brain barrier is progressively compromised. These age-related neurovascular changes are accompanied by neuroinflammation and deficits in common and spontaneous behaviors in mice. We found, however, that exercise from middle to older age preserves the cerebrovascular health, prevents behavioral deficits and reduces the age-related neuroinflammation in the cortex and hippocampus in aged mice. Mice deficient in Apoe, a gene associated with longevity and Alzheimer’s disease, are resistant to the beneficial effects of exercise, suggesting a possible mediating role for APOE in the maintenance and function of the neurovascular system during aging.

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Exactly what this means for people with APOE gene variants like APOE4 isn't clear, at least to me. Would exercise be somewhat of a waste of time for these people, unable to preserve cognitive health, like in the APOE-deficient mice? Or would exercise be more important for APOE4 carriers, to get the most from their relatively-impaired APOE activity on the brain?

Hey Dean,
Mechanism aside, exercise is one of the few, if not only, standard life-style element that is clearly associated with greater benefit in APOE-epsilon-4 carriers than in non-carriers. (Some studies, in fact, show zero benefit of exercise with respect to dementia risk in 3/3s.)
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Mechanism aside, exercise is one of the few, if not only, standard life-style element that is clearly associated with greater benefit in APOE-epsilon-4 carriers than in non-carriers. (Some studies, in fact, show zero benefit of exercise with respect to dementia risk in 3/3s.)


Thanks Zeta. You are absolutely right. I shouldn't have left the question of exercise's value for APOE-e4 carriers as ambiguous in my original post. It appears pretty definitive from the evidence (e.g. [1-4]) that exercise is relatively more beneficial for APOE-e4 carriers than non-carriers when it comes to preserving cognitive function and avoiding Alzheimer's disease.





[1] Arch Neurol. 2012 May;69(5):636-43.

Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid



Head D(1), Bugg JM, Goate AM, Fagan AM, Mintun MA, Benzinger T, Holtzman DM,

Morris JC.


Author information:

(1)Department of Psychology, Washington University, St Louis, MO 63130, USA.



OBJECTIVE: APOE ε4 status has been associated with greater cortical amyloid

deposition, whereas exercise has been associated with less in cognitively normal

adults. The primary objective here was to examine whether physical exercise

moderates the association between APOE genotype and amyloid deposition in

cognitively normal adults.

DESIGN: APOE genotyping data and answers to a questionnaire on physical exercise

engagement over the last decade were obtained in conjunction with cerebrospinal

fluid (CSF) samples and amyloid imaging with carbon 11-labeled Pittsburgh

Compound B ([(11)C]PiB) positron emission tomography. Participants were

classified as either low or high exercisers based on exercise guidelines of the

American Heart Association.

SETTING: Knight Alzheimer's Disease Research Center at Washington University, St

Louis, Missouri.

PARTICIPANTS: A total of 201 cognitively normal adults (135 of whom were women)

aged 45 to 88 years were recruited from the Knight Alzheimer's Disease Research

Center. Samples of CSF were collected from 165 participants. Amyloid imaging was

performed for 163 participants.

RESULTS: APOE ε4 carriers evidenced higher [(11)C]PiB binding (P<.001) and lower

CSF Aβ42 levels (P<.001) than did noncarriers. Our previous findings of higher

[(11)C]PiB binding (P=.005) and lower CSF Aβ42 levels (P=.009) in more sedentary

individuals were replicated. Most importantly, we observed a novel interaction

between APOE status and exercise engagement for [(11)C]PiB binding (P=.008) such

that a more sedentary lifestyle was significantly associated with higher

[(11)C]PiB binding for ε4 carriers (P=.013) but not for noncarriers (P=.20). All

findings remained significant after controlling for age; sex; educational level;

body mass index; the presence or history of hypertension, diabetes mellitus,

heart problems, or depression; and the interval between assessments.

CONCLUSION: Collectively, these results suggest that cognitively normal sedentary

APOE ε4-positive individuals may be at augmented risk for cerebral amyloid



PMCID: PMC3583203

PMID: 22232206



[2] Alzheimers Dement. 2009 Jul;5(4):287-94. doi: 10.1016/j.jalz.2009.02.006.

Exercise improves cognition and hippocampal plasticity in APOE epsilon4 mice.


Nichol K(1), Deeny SP, Seif J, Camaclang K, Cotman CW.


Author information:

(1)Institute for Brain Aging and Dementia, University of California, Irvine, CA,

USA. k8nichol@gmail.com


BACKGROUND: Human studies on exercise, cognition, and apolipoprotein E (APOE)

genotype show that epsilon4 carriers may benefit from regular physical activity.

METHODS: We examined voluntary wheel-running, memory, and hippocampal plasticity

in APOE epsilon3 and APOE epsilon4 transgenic mice at 10-12 months of age.

RESULTS: Sedentary epsilon4 mice exhibited deficits in cognition on the

radial-arm water maze (RAWM), a task dependent on the hippocampus. Six weeks of

wheel-running in epsilon4 mice resulted in improvements on the RAWM to the level

of epsilon3 mice. Hippocampal brain-derived neurotrophic factor (BDNF) levels

were similar in epsilon3 and epsilon4 mice, and after exercise BDNF was similarly

increased in both epsilon3 and epsilon4 mice. In sedentary epsilon4 mice,

tyrosine kinase B (Trk B) receptors were reduced by 50%. Exercise restored Trk B

in epsilon4 mice to the level of epsilon3 mice, and in epsilon4 mice, exercise

dramatically increased synaptophysin, a marker of synaptic function.

CONCLUSIONS: Our results support the hypothesis that exercise can improve

cognitive function, particularly in epsilon4 carriers.


PMCID: PMC4105011

PMID: 19560099



[3] Mol Psychiatry. 2013 Aug;18(8):875-81. doi: 10.1038/mp.2012.107. Epub 2012 Aug



Physical activity and amyloid-β plasma and brain levels: results from the

Australian Imaging, Biomarkers and Lifestyle Study of Ageing.


Brown BM(1), Peiffer JJ, Taddei K, Lui JK, Laws SM, Gupta VB, Taddei T, Ward VK,

Rodrigues MA, Burnham S, Rainey-Smith SR, Villemagne VL, Bush A, Ellis KA,

Masters CL, Ames D, Macaulay SL, Szoeke C, Rowe CC, Martins RN.


Author information:

(1)Centre of Excellence for Alzheimer's Disease Research and Care, School of

Medical Sciences, Edith Cowan University, Joondalup, WA, Australia.


Previous studies suggest physical activity improves cognition and lowers

Alzheimer's disease (AD) risk. However, key AD pathogenic factors that are

thought to be influenced by physical activity, particularly plasma amyloid-β (Aβ)

and Aβ brain load, have yet to be thoroughly investigated. The objective of this

study was to determine if plasma Aβ and amyloid brain deposition are associated

with physical activity levels, and whether these associations differed between

carriers and non-carriers of the apolipoprotein E (APOE) ε4 allele. Five-hundred

and forty six cognitively intact participants (aged 60-95 years) from the

Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) were included

in these analyses. Habitual physical activity levels were measured using the

International Physical Activity Questionnaire (IPAQ). Serum insulin, glucose,

cholesterol and plasma Aβ levels were measured in fasting blood samples. A

subgroup (n=116) underwent (11)C-Pittsburgh compound B (PiB) positron emission

tomography (PET) scanning to quantify brain amyloid load. Higher levels of

physical activity were associated with higher high density lipoprotein (HDL)

(P=0.037), and lower insulin (P<0.001), triglycerides (P=0.019) and Aβ1-42/1-40

ratio (P=0.001). After stratification of the cohort based on APOE ε4 allele

carriage, it was evident that only non-carriers received the benefit of reduced

plasma Aβ from physical activity. Conversely, lower levels of PiB SUVR

(standardised uptake value ratio) were observed in higher exercising APOE ε4

carriers. Lower plasma Aβ1-42/1-40 and brain amyloid was observed in those

reporting higher levels of physical activity, consistent with the hypothesis that

physical activity may be involved in the modulation of pathogenic changes

associated with AD.


PMID: 22889922



[4] Med Sci Sports Exerc. 2007 Jan;39(1):199-207.

Cognitive performance in older women relative to ApoE-epsilon4 genotype and

aerobic fitness.


Etnier JL(1), Caselli RJ, Reiman EM, Alexander GE, Sibley BA, Tessier D, McLemore



Author information:

(1)Department of Exercise and Sport Science, University of North Carolina,

Greensboro, NC 27402, USA. JLEtnier@uncg.edu


INTRODUCTION: Apolipoprotein E (ApoE) genotype and aerobic fitness are each

associated with cognitive performance in older adults. However, their potentially

interactive effects on cognitive performance have not been examined.

PURPOSE: The primary purpose of this study was to determine whether ApoE genotype

and aerobic fitness interact to uniquely impact memory performance and executive

functioning. A secondary purpose was to examine the interactive effects on other

measures of cognition to provide a more comprehensive assessment of cognitive

abilities across a broad range of functions.

METHODS: Community-dwelling, cognitively normal older women (N = 90) provided

blood samples to allow for assessment of ApoE genotype, completed cognitive

tests, and performed a maximal aerobic fitness test. Primary outcome variables

were the auditory verbal learning test (AVLT), the complex figures test (CFT),

and the Wisconsin card-sorting task (WCST). Secondary outcome variables were the

block design test and the paced auditory serial addition task (PASAT).

RESULTS: Regression analyses indicated that aerobic fitness was associated with

significantly better performance on measures of the AVLT, the CFT, and the PASAT

for the ApoE-epsilon4 homozygotes.

CONCLUSION: The preliminary findings from this study support the possibility that

aerobic fitness is positively associated with the memory performance of those

individuals at most genetic risk for Alzheimer disease.


PMID: 17218903

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