Cited by 212Dementia and Cognitive Impairment ResearchPhysical Activity and HealthAlzheimer's disease research and treatments

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Physical Activity, Brain Volume, and Dementia Risk: The Framingham Study

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Tan, Zaldy S., Spartano, Nicole L., Beiser, Alexa S., DeCarli, Charles, Auerbach, Sanford H., Vasan, Ramachandran S., Seshadri, Sudha·2016·The Journals of Gerontology Series A: Biological Sciences and Medical Sciences

DOI 10.1093/gerona/glw130PMC PMC6075525

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Abstract

BACKGROUND: Several longitudinal studies found an inverse relationship between levels of physical activity and cognitive decline, dementia, and/or Alzheimer's disease (AD), but results have been inconsistent. We followed an older, community-based cohort for over a decade to examine the association of physical activity with the risk of incident dementia and subclinical brain MRI markers of dementia. METHODS: The physical activity index (PAI) was assessed in the Framingham Study Original and Offspring cohorts, aged 60 years or older. We examined the association between PAI and risk of incident all-cause dementia and AD in participants of both cohorts who were cognitively intact and had available PAI (n = 3,714; 54% women; mean age = 70±7 years). We additionally examined the association between PAI and brain MRI in the Offspring cohort (n = 1,987). RESULTS: Over a decade of follow-up, 236 participants developed dementia (188 AD). Participants in the lowest quintile of PAI had an increased risk of incident dementia compared with those in higher quintiles (hazard ratio [HR] = 1.50, 95% confidence interval [CI] = 1.04-1.97, p = .028) in a multivariable-adjusted model. Secondary analysis revealed that this relation was limited to participants who were apolipoprotein (APO)E ε4 allele noncarriers (HR = 1.58, 95% CI = 1.08-2.32; p = .018) and strongest in participants aged 75 years or older. PAI was also linearly related to total brain and hippocampal volumes (β ± SE = 0.24±0.06; p < .01 and 0.004±0.001; p = .003, respectively). CONCLUSION: Low physical activity is associated with a higher risk for dementia in older individuals, suggesting that a reduced risk of dementia and higher brain volumes may be additional health benefits of maintaining physical activity into old age.

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“association between physical activity and dementia risk [40].”
Background
Autonomic Imbalance and Risk of Dementia and Stroke: The Framingham Study
Weinstein, G., Davis‐Plourde, K. L., Beiser, A., & Seshadri, S. S. (2021) · Stroke · doi:10.1161/strokeaha.120.030601 · Cited by 37
Self-citation
Early Life Stress Affects Bdnf Regulation: A Role for Exercise Interventions
Campbell, T. S., Donoghue, K. M., Ghosh, U., Nelson, C. M., & Roth, T. L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911729 · Cited by 39
“A 2017 study following the natural aging of older adults (for ~10 years) showed that exercise is positively related to total cerebral and hippocampal volumes, and negatively related to developing Alzheimer’s Disease and dementia [100].”
Background
The Beneficial Role of Exercise on Treating Alzheimer’s Disease by Inhibiting β-Amyloid Peptide
Tan, Z., Dong, F., Wu, L., Feng, Y.-S., & Zhang, F. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02514-7 · Cited by 39
Self-citation
Effect of Interval and Continuous Aerobic Training on Basal Serum and Plasma Brain-Derived Neurotrophic Factor Values in Seniors: A Systematic Review of Intervention Studies
Enette, L., Vogel, T., Fanon, J. L., & Lang, P. O. (2017) · Rejuvenation Research · doi:10.1089/rej.2016.1886 · Cited by 36
“…and IAT or CAT of high intensity facilitates the upregulation of BDNF. 81,82 This was conﬁrmed by Schmolesky et al. 66 (high workload and intensity generated a positive BDNF response to exercise) and Tan et al. 51 ( i.e ., low workload and intensity were associated with higher risk of dementia).”
Influential
Prospective Analysis of Leisure-Time Physical Activity in Midlife and Beyond and Brain Damage on MRI in Older Adults
Palta, P., Sharrett, A. R., Gabriel, K. P., Gottesman, R. F., Folsom, A. R., Power, M. C., Evenson, K. R., Jack, C. R., Knopman, D. S., Mosley, T. H., et al. (2021) · Neurology · doi:10.1212/wnl.0000000000011375 · Cited by 34
“categorized in sex-specific quintiles were linearly associated with total brain and hippocampal volumes.(32) However,”
Background
Dose‐response relationship between late‐life physical activity and incident dementia: A pooled analysis of 10 cohort studies of memory in an international consortium
Wu, W., Ding, D., Zhao, Q., Xiao, Z., Luo, J., Ganguli, M., Hughes, T. F., Jacobsen, E. P., Haan, M. N., van Dang, K., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12628 · Cited by 34
Longitudinal Associations between the Neighborhood Built Environment and Cognition in US Older Adults: The Multi-Ethnic Study of Atherosclerosis
Besser, L. M., Chang, L., Hirsch, J. A., Rodrı́guez, D. A., Renne, J. L., Rapp, S. R., Fitzpatrick, A. L., Heckbert, S. R., Kaufman, J. D., & Hughes, T. M. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18157973 · Cited by 31
“One potential mechanism to explain these associations is that mixed land uses, green spaces, and greater street connectivity encourage neighborhood walking and thereby increased PA, which has been associated with better cognition and lower dementia risk [12,13].”
Background
Larger Lateral Prefrontal Cortex Volume Predicts Better Exercise Adherence Among Older Women: Evidence From Two Exercise Training Studies
Best, J. R., Chiu, B. K., Hall, P. A., & Liu-Ambrose, T. Y. L. (2017) · The Journals of Gerontology Series A · doi:10.1093/gerona/glx043 · Cited by 30
“Engaging in regular exercise imparts numerous benefits for older adults, including reduced dementia risk (1,2), improved cardiovascular health and superior physical functioning (3).”
Background
Physical activity across adulthood and subjective cognitive function in older men
Fondell, E., Townsend, M. K., Unger, L. D., Okereke, O. I., Grodstein, F., Ascherio, A., & Willett, W. C. (2017) · European Journal of Epidemiology · doi:10.1007/s10654-017-0331-2 · Cited by 35
“In The Framingham study with over 10 years of follow-up, the authors found that higher levels of physical activity was associated with a lower risk of dementia in older individuals and among those who were not APOE e4 carriers [33].”
Body composition and genetic lipodystrophy risk score associate with nonalcoholic fatty liver disease and liver fibrosis
Chen, V. L., Wright, A. P., Halligan, B., Chen, Y., Du, X., Handelman, S. K., Long, M. T., Kiel, D. P., & Speliotes, E. K. (2019) · Hepatology Communications · doi:10.1002/hep4.1391 · Cited by 28
“The physical activity index is a composite score calculated based on participant responses to questions regarding different levels of physical activity and sleep patterns over a 24-hour period.(26) Grip strength and quadriceps strength were measured as described.”
Method
Physical Activity and Trajectory of Cognitive Change in Older Persons: Mayo Clinic Study of Aging
Krell‐Roesch, J., Syrjanen, J. A., Bezold, J., Trautwein, S., Barisch‐Fritz, B., Boes, K., Wöll, A., Forzani, E., Kremers, W. K., Machulda, M. M., et al. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200959 · Cited by 34
Associations between psychological intervention for anxiety disorders and risk of dementia: a prospective cohort study using national health-care records data in England
Stott, J. C. H., Saunders, R., Desai, R., Bell, G., Fearn, C., Buckman, J. E. J., Brown, B., Nurock, S., Michael, S., Ware, P., et al. (2022) · The Lancet Healthy Longevity · doi:10.1016/s2666-7568(22)00242-2 · Cited by 34
“Specifically, this association could operate through a range of distinct biological (eg, cardio-metabolic factors 27 ), psychosocial (eg, repetitive negative thinking 28 ), and lifestyle (eg, physical activity 29 ) pathways.”
Background
Examination of potentially modifiable dementia risk factors across the adult life course: The Framingham Heart Study
Hwang, P. H., Ang, T. F. A., De Anda‐Duran, I., Liu, X., Liu, Y., Gurnani, A., Mez, J., Auerbach, S., Joshi, P., Yuan, J., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12940 · Cited by 28
Self-citation
Physical activity and depression in older adults with and without cognitive impairment
Yuenyongchaiwat, K., Pongpanit, K., & Hanmanop, S. (2018) · Dementia & Neuropsychologia · doi:10.1590/1980-57642018dn12-010002 · Cited by 29
Physical activity in later life and risk of dementia: Findings from a population-based cohort study
Feter, N., Mielke, G. I., Leite, J. S., Brown, W. J., Coombes, J. S., & Rombaldi, A. J. (2020) · Experimental Gerontology · doi:10.1016/j.exger.2020.111145 · Cited by 29
Cultural Engagement and Incidence of Cognitive Impairment: A 6-year Longitudinal Follow-up of the Japan Gerontological Evaluation Study (JAGES)
Sugita, A., Ling, L., Tsuji, T., Kondo, K., & Kawachi, I. I. (2020) · Journal of Epidemiology · doi:10.2188/jea.je20190337 · Cited by 33
The Therapeutic Role of Exercise and Probiotics in Stressful Brain Conditions
Martínez‐Guardado, I., Arboleya, S., Pérez, F. J. G., Kaliszewska, A., Gueimonde, M., & Arias, N. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073610 · Cited by 27
Understanding How Physical Exercise Improves Alzheimer’s Disease: Cholinergic and Monoaminergic Systems
Zong, B., Yu, F., Zhang, X., Zhao, W., Sun, P., Li, S., & Li, L. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.869507 · Cited by 31
The Brain Health Champion study: Health coaching changes behaviors in patients with cognitive impairment
Schwartz, H. E. M., Bay, C. P., McFeeley, B. M., Krivanek, T. J., Daffner, K. R., & Gale, S. A. (2019) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2019.09.008 · Cited by 25
Estimating the effect of physical activity on cognitive function within the UK Biobank cohort
Campbell, T., & Cullen, B. (2023) · International Journal of Epidemiology · doi:10.1093/ije/dyad009 · Cited by 31
The relationship between physical activity, apolipoprotein E ε4 carriage, and brain health
de Frutos‐Lucas, J., Cuesta, P., López‐Sanz, D., Peral‐Suárez, Á., Cuadrado‐Soto, E., Ramírez‐Toraño, F., Brown, B. M., Serrano, J. M., Laws, S. M., Rodríguez‐Rojo, I. C., et al. (2020) · Alzheimer s Research & Therapy · doi:10.1186/s13195-020-00608-3 · Cited by 27
“Most studies investigating the relationship between AD incidence and PA have concluded that only APOE ε4 non-carriers benefit from reduced AD risk at greater levels of PA [9, 49, 50], although there are some exceptions [51, 52].”
BackgroundResult
Physical Activity Over the Adult Life Course and Risk of Dementia in the Framingham Heart Study
Marino, F., Lyu, C., Li, Y., Liu, T., Au, R., & Hwang, P. H. (2025) · JAMA Network Open · doi:10.1001/jamanetworkopen.2025.44439 · Cited by 23
White Matter Integrity Underlies the Physical-Cognitive Correlations in Subjective Cognitive Decline
Wei, Y., Hsu, C. H., Huang, W., Chen, Y.-L., Lin, C., Chen, C., Lin, C., Shyu, Y., & Lin, C. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.700764 · Cited by 23
Bone Mineral Density Measurements and Association With Brain Structure and Cognitive Function
Stefanidou, M., O’Donnell, A., Himali, J. J., DeCarli, C. S., Satizábal, C. L., Beiser, A., Seshadri, S. S., & Tan, Z. S. (2021) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0000000000000453 · Cited by 22
Self-citation
Relationship between objectively measured physical activity on neuropathology and cognitive outcomes in older adults: Resistance versus resilience?
Memel, M., Buchman, A. S., Bennett, D. A., & Casaletto, K. B. (2021) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12245 · Cited by 20
What do we know from clinical trials on exercise and Alzheimer's disease?
Shen, Y., & Li, R. (2016) · Journal of sport and health science/Journal of Sport and Health Science · doi:10.1016/j.jshs.2016.10.002 · Cited by 22
“subclinical brain magnetic resonance imaging markers of dementia.(4) The study found that physical activity affected the size of the hippocampus, which controls short-term memory.”
Background
Associations between psychological therapy outcomes for depression and incidence of dementia
John, A., Saunders, R., Desai, R., Bell, G., Fearn, C., Buckman, J. E. J., Brown, B., Nurock, S., Michael, S., Ware, P., et al. (2022) · Psychological Medicine · doi:10.1017/s0033291722002537 · Cited by 28
“low levels of physical activity (Tan et al., 2017), etc.”
Objective Physical Activity Accumulation and Brain Volume in Older Adults: An MRI and Whole-Brain Volume Study
Neves, L. M., Ritti‐Dias, R. M., Juday, V., Marquesini, R., Gerage, A. M., Laurentino, G. C., Nunes, R. H., Stubbs, B., & Ugrinowitsch, C. (2022) · The Journals of Gerontology Series A · doi:10.1093/gerona/glac150 · Cited by 20
Clinical Perspectives on Cardiac Rehabilitation After Heart Failure in Elderly Patients with Frailty: A Narrative Review
Tsukakoshi, D., Yamamoto, S., Takeda, S., Furuhashi, K., & Sato, M. (2022) · Therapeutics and Clinical Risk Management · doi:10.2147/tcrm.s350748 · Cited by 20
“Since high activity is known to have a positive effect on brain capacity and Aβ, not only the amount of exercise during the intervention but also to increase it in daily life should be managed.(94,95) For the cognitive function of elderly patients with mild cognitive impairment or dementia, the amount of exercise and…”
Background
Effects of health risk assessment and counselling on physical activity in older people: A pragmatic randomised trial
Herghelegiu, A. M., Moser, A., Prada, G. I., Born, S., Wilhelm, M., & Stuck, A. E. (2017) · PLoS ONE · doi:10.1371/journal.pone.0181371 · Cited by 20
“…adults, PA has shown additional benefits that include the prevention or delay of functional decline [7,8], protective effects on cognitive function [9], mood improvement in depressive disorders [10], reduced fear of falling and improved balance [11], and prevention of fractures by increasing…”
Association of cardiovascular health with the risk of dementia in older adults
Cho, S., Yang, P., Kim, D., You, S. C., Sung, J., Jang, E., Yu, H. T., Kim, T., Pak, H., Lee, M., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-20072-3 · Cited by 22
Increased Physical Fitness Is Associated with Higher Executive Functioning in People with Dementia
Hollamby, A., Davelaar, E. J., & Cadar, D. (2017) · Frontiers in Public Health · doi:10.3389/fpubh.2017.00346 · Cited by 21
“(56) observed a positive linear association between (selfreported) PA and total brain and hippocampal volumes together with a reduced risk of dementia.”
Background
Associations of Physical Activity with Alzheimer’s Disease Pathologies and Cognition: The CABLE Study
Shuang, Z., Zhao, B. T., Ma, Y., Sun, Y., Zhao, Y., Liu, W., Ou, Y., Dong, Q., Tan, L., & Yu, J. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220389 · Cited by 17
Early Mobilization After Stroke Is Not Associated With Cognitive Outcome
Cumming, T. B., Bernhardt, J. A., Lowe, D., Collier, J. M., Dewey, H. M., Langhorne, P., Thrift, A. G., Green, A., Mohanraj, R., Kramer, S. F., et al. (2018) · Stroke · doi:10.1161/strokeaha.118.022217 · Cited by 17
Self-Reported Physical Activity and Relations to Growth and Neurotrophic Factors in Diabetes Mellitus: The Framingham Offspring Study
Spartano, N. L., Davis‐Plourde, K. L., Himali, J. J., Murabito, J. M., Vasan, R. S., Beiser, A., & Seshadri, S. S. (2019) · Journal of Diabetes Research · doi:10.1155/2019/2718465 · Cited by 17
“These participants are the offspring and offspring’s spouses of the Original Framingham Heart Study cohort.”
MethodInfluentialSelf-citation
Cross-sectional associations between 24-hour time-use composition, grey matter volume and cognitive function in healthy older adults
Mellow, M. L., Dumuid, D., Olds, T., Stanford, T., Dorrian, J., Wade, A. T., Fripp, J., Xia, Y., Goldsworthy, M. R., Karayanidis, F., et al. (2024) · International Journal of Behavioral Nutrition and Physical Activity · doi:10.1186/s12966-023-01557-4 · Cited by 16
“, 70-80 years) which may have more progressed brain atrophy in comparison (4, 7), or in samples with a wider age range (e.”
BackgroundMethodResultInfluential
Cardiometabolic determinants of early and advanced brain alterations: Insights from conventional and novel MRI techniques
Vergoossen, L. W. M., Jansen, J. F. A., Backes, W. H., & Schram, M. T. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.04.001 · Cited by 16
“, 2014), Framingham (Spartano et al., 2019; Tan et al., 2017), LADIS (Baezner et al.”
Influential
The Effects of Nordic Walking With Poles With an Integrated Resistance Shock Absorber on Cognitive Abilities and Cardiopulmonary Efficiency in Postmenopausal Women
Domaszewska, K., Koper, M., Wochna, K., Czerniak, U., Marciniak, K., Wilski, M., & Bukowska, D. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.586286 · Cited by 18
“There are several lines of evidence to indicate that physical exercise not only can generally slow down aging and prevent chronic, psychiatric and neurodegenerative diseases, but is very important in maintaining normal brain function or softening its progressive loss (Haskell et al., 2007; Pedersen and Saltin, 2015; T…”
Background
Adherence of Mobile App-Based Surveys and Comparison With Traditional Surveys: eCohort Study
Pathiravasan, C. H., Zhang, Y., Trinquart, L., Benjamin, E. J., Borrelli, B., McManus, D. D., Kheterpal, V., Lin, H., Sardana, M., Hammond, M. M., et al. (2021) · Journal of Medical Internet Research · doi:10.2196/24773 · Cited by 17
“We calculated PAI as a weighted composite score [27-29] of activity levels with corresponding weights of 1 (for sleep), 1.”
Self-citation
Biopsychosocial Correlates of Subjective Cognitive Decline and Related Worry in the Canadian Longitudinal Study on Aging
Hopper, S., Hammond, N. G., Taler, V., & Stinchcombe, A. (2022) · Gerontology · doi:10.1159/000524280 · Cited by 15
Fatness, fitness and the aging brain: A cross sectional study of the associations between a physiological estimate of brain age and physical fitness, activity, sleep, and body composition
Wing, D., Eyler, L. T., Lenze, E. J., Wetherell, J. L., Nichols, J. F., MEEUSEN, R. R., Godino, J., Shimony, J. S., Snyder, A. Z., Nishino, T., et al. (2022) · Neuroimage Reports · doi:10.1016/j.ynirp.2022.100146 · Cited by 16
“Large cohort studies have found strong correlations between physical fitness and activity levels and both brain volume and risk of developing cognitive dysfunction (Tan et al., 2017; Zhu et al., 2015).”
Background

Authors: Tan, Z. S., Spartano, N. L., Beiser, A. S., DeCarli, C., Auerbach, S. H., Vasan, R. S., & Seshadri, S.
Affiliations: University of California, Los Angeles (US)
Framingham Heart Study (US)
Boston University (US)
University of California, Davis (US)
ORCID: Tan, Zaldy S.
Spartano, Nicole L.
Beiser, Alexa S.
DeCarli, Charles
Auerbach, Sanford H.
Vasan, Ramachandran S.
Seshadri, Sudha
Venue: The Journals of Gerontology Series A: Biological Sciences and Medical Sciences
Publisher: Oxford University Press (OUP)
Published: 2016-07-15
Volume: 72
Issue: 6
Pages: glw130
ISSN: 1079-5006 (ISSN-L)
1758-535X
DOI: 10.1093/gerona/glw130
PMC: PMC6075525
OpenAlex: W2468595961
Cited by: 212
References: 38
Citations by year: 2026: 10 · 2025: 24 · 2024: 20 · 2023: 20 · 2022: 35 · 2021: 25 · 2020: 21 · 2019: 25 · 2018: 18 · 2017: 13 · 2016: 1
FWCI: 16.88
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: The Journals of Gerontology Series A (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: National Institutes of Health
National Heart, Lung, and Blood Institute (NIH/NHLBI, HHSN268201500001I, N01-HC-25195, N01HV28178, R01HL093029, R01 HL131029, U01 HL096917, 2K24HL04334)
National Institute on Aging (R01 AG016495, AG008122, AG031287, AG047645)
National Institute of Neurological Disorders and Stroke (NINDS, R01 NS017950)
American Heart Association (AHA Award 11CRP4930020, 16MCPRP30310001)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Physical Activity and Health
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords: physical activity, dementia risk, Alzheimer's disease, brain volume, hippocampal volume, APOE ε4, older adults, cognitive decline, physical activity index, brain MRI markers, Framingham Heart Study
MeSH terms: Age Factors, Aged, Alleles, Alzheimer Disease, Brain, Dementia, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Risk, United States, Cohort Studies, Exercise, Apolipoprotein E4

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Physical Activity, Brain Volume, and Dementia Risk: The Framingham Study

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