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Physical Activity, Brain Volume, and Dementia Risk: The Framingham Study
Open accessAbstract
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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“In contrast, physical activity appears to decrease risk. [119][120]0][121][122][123][124][125][126][127][128]”
From 2023 Alzheimer's disease facts and figures (2023) · cites this paper as [122]
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“Collectively, this suggests that eating a heart-healthy diet [172,173,174,175,176] and increasing physical activity [177,178,179,180] could delay the onset of AD.”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [178]
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Nehrkorn-Bailey, A. M., Rodriguez, D., Forsyth, G., Braun, B., Burke, K. M., & Diehl, M. K. (2023) · Journal of Aging and Physical Activity · doi:10.1123/japa.2022-0133 · Cited by 13
Clinical information prompt‑driven retinal fundus image for brain health evaluation
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Self-citationModeling Brain Volume Using Deep Learning-Based Physical Activity Features in Patients With Dementia
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“Tan et al. (2017) also studied the relationship between physical activity and brain volume, particularly in a region specific to dementia, the hippocampus.”
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“Varied exercise intensities can contribute to brain volume maintenance, 45 so it is possible that the typical intensity of PA performed was insufficient to alter brain volume.”
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24‐hour activity cycle behaviors and gray matter volume in mild cognitive impairment
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Physiotherapy for Healthy Aging
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“These data contrast with published evidence linking fitness and brain health, both in terms of the volume of various brain structures (6) and cognitive performance (10).”
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BackgroundAssociation of cognitive function and phase angle in older adults with cognitive impairment
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Self-citationSeven-Day Pedometer-Assessed Step Counts and Brain Volume: A Population-Based Observational Study
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“Previous studies found that PA could protect cognition by improving the structure and function of the brain (Kennedy et al., 2017; Kishimoto et al., 2016; Mehlig et al., 2014; Tan et al., 2017).”
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“The brain phenotypes mediating this reduced risk for AD, the most common cause of dementia, are not fully established, but some studies have reported preservation of brain volume with PA (Erickson et al., 2010; Tan et al., 2016).”
BackgroundLongitudinal associations between exercise and biomarkers in autosomal dominant Alzheimer's disease
Sewell, K. R., Doecke, J. D., Xiong, C., Benzinger, T. L. S., Masters, C. L., Laske, C., Jucker, M., Lopera, F. J., Gordon, B. A., Llibre‐Guerra, J. J., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14270 · Cited by 6
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“However, certain studies demonstrate that regular physical activity contributes to reducing the risk of the onset of dementia (Tan et al., 2016; Mabire et al., 2018).”
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“On multivariable adjustment, fasting plasma insulin levels were inversely associated with age, male sex (indicating higher levels in women), and the Physical Activity Index; whereas waist circumference, the total/HDL cholesterol ratio, and triglyceride levels were positively associated with fasting plasma insulin leve…”
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“However, caution is needed when interpreting the longitudinal beneficial effects of physical activity on the risk of cognitive decline and dementia since several studies have found that when longer follow ups (over 10 years) are carried out, the protective effect of physical activity diminishes and becomes weak or non…”
BackgroundMinimum physical activities protective against Alzheimer’s disease in late life: a systematic review
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“Reduced physical activity and immobility is considered nowadays as one of the most important risk factors of cognitive deterioration 24,41,42 and our results also highlighted its crucial and leading predictive value in the development of SCC.”
BackgroundHigher vitamin B 12 from mid‐ to late life is related to slower rates of cognitive decline
Marino, F., Rogers, G. T., Miller, J. W., Selhub, J., Mez, J. B., Crane, P. K., Mukherjee, S., Saykin, A. J., Hohman, T. J., Trittschuh, E. H., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70864 · Cited by 3
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“[8] reviewed data on a potential relationship between PA and risk of dementia collected in the Framingham study.”
BackgroundPhysical Activities and Prevention of Neurodegenerative Diseases
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Barnes, J. N., Burns, J. M., Bamman, M. M., Billinger, S. A., Bodine, S. C., Booth, F. W., Brassard, P., Clemons, T. A., Fadel, P. J., Geiger, P. C., et al. (2022) · Brain Plasticity · doi:10.3233/bpl-220146 · Cited by 4
“ory function during normal aging [14], and reduces 66 the incidence of AD [15, 16].”
BackgroundShapira‐Daniels, A., Kornej, J., Spartano, N. L., Wang, X., Zhang, Y., Pathiravasan, C. H., Liu, C., Trinquart, L., Borrelli, B., McManus, D. D., et al. (2023) · Journal of Medical Internet Research · doi:10.2196/43123 · Cited by 3
“This questionnaire, which has been used in other FHS studies, asked participants to estimate the number of hours in a typical day that they spent performing varying levels of physical activity over the past year [25,26].”
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“The Framingham and Framingham Offspring Study cohorts (aged 60 years or older) found a linear association between physical activity levels and total cerebral and hippocampal brain volume [115].”
MethodThe Link Between Exercise and Mediation of Alzheimer's Disease and Neurodegenerative Diseases
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Savignac, C., Villeneuve, S., Badhwar, A., Saltoun, K., Shafighi, K., Zajner, C., Sharma, V., Taliun, S. A. G., Farhan, S. M. K., Poirier, J., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.03.15.484482 · Cited by 3
“The 540 variability of the protective effect of physical activity on dementia risk when stratifying 541 participants by ɛ4 status might be taken to suggest that APOE ɛ2 is driving the relationship 542 between physical activity and cognitive performance [67-71].”
BackgroundWawrzyniak, A. J. (2017) · Springer eBooks · doi:10.1007/978-1-4614-6439-6_803-2 · Cited by 3
Ishizuka, N., Akasaka, H., Sato, M., Sato, Y., Hosokawa, K., Takahashi, J., Yonezawa, H., Terayama, Y., Ohara, T., Honda, T., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-04659-0 · Cited by 2
“It is also possible that frailty itself, through mechanisms such as physical inactivity or systemic inflammation, contributes to changes in both BMI and brain volume 5,51 .”
Paulsen, A. J., Driscoll, I. F., Breidenbach, B. M., Glittenberg, M., Lose, S. R., Ma, Y., Sager, M. A., Carlsson, C. M., Gallagher, C. L., Hermann, B. P., et al. (2025) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.70122 · Cited by 2
“…levels of physical activity (PA) and better cardiorespiratory fitness (CRF) may positively alter some aspects of AD neuropathology—that is, less atrophy, 8,9 modifying influences on biomarker accumulation, 10,11 and protecting against age-related cognitive decline 8,9,12–15 —thereby reducing risk.”
Makino, K., Lee, S., Bae, S., Harada, K., Chiba, I., Katayama, O., Tomida, K., Morikawa, M., Yamashiro, Y., Sudo, M., et al. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.882562 · Cited by 2
Increased Likelihood of Dementia with Coexisting Atrophy of Multiple Regions of Interest
Kim, R. E. Y., Lee, M., Kang, D. W., Wang, S., Kim, D., & Lim, H. K. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230602 · Cited by 2
Khattak, H. G., Arshad, H., Anwar, K., & Ali, M. Q. (2024) · Journal of Bahria University Medical and Dental College · doi:10.51985/jbumdc2023172 · Cited by 2
Elsworthy, R. J., Jong, S. T., Hanson, S., Shannon, O. M., Jennings, A., Gillings, R., Siervo, M., Hornberger, M., Hardeman, W., Mathers, J. C., et al. (2024) · Frontiers in Public Health · doi:10.3389/fpubh.2024.1371453 · Cited by 2
Age-related volume decrease in subcortical gray matter is a part of healthy brain aging in men
Perić, R., Romčević, I., Mastilović, M., Starčević, I., & Boban, J. M. (2024) · Irish Journal of Medical Science (1971 -) · doi:10.1007/s11845-024-03840-0 · Cited by 2
Ding, H., Brown, S., Paquette, D. R., Orwig, T. A., Spartano, N. L., & Lin, H. (2025) · Journal of Medical Internet Research · doi:10.2196/72946 · Cited by 2
“Despite the value of existing studies, most have relied on self-reported assessments of physical activity [8-11].”
Self-citationFrith, E., & Loprinzi, P. D. (2018) · Cardiopulmonary Physical Therapy Journal · doi:10.1097/cpt.0000000000000069 · Cited by 2
Felisatti, F., Chauveau, L., Marchant, N. L., Collette, F., Demnitz‐King, H., Whitfield, T. J., Requier, F., Mézenge, F., Landeau, B., Palix, C., et al. (2023) · medRxiv · doi:10.1101/2023.07.17.23292755 · Cited by 2
Kinoshita‐Katahashi, N., Shibata, Y., Yasuda, H., Ishikawa, S., Gotoh, T., Nakamura, Y., Kayaba, K., & Ojima, T. (2022) · Clinical and Experimental Nephrology · doi:10.1007/s10157-022-02301-1 · Cited by 1
“In one study in which the daily physical activity of 383 residents with eGFR 60 ml/min/1.73 m2 in the USA was measured by means of an accelerometer, estimation of the exponentiation of linear contrasts of the Cox regression coefficients showed that the risk of death was significantly reduced when 2 min/h of sedentary…”
MethodInfluentialCai, Y., Zhou, J., Scott, P. W., Tian, Q., Wanigatunga, A. A., Lipsitz, L. A., Simonsick, E. M., Resnick, S. M., Ferrucci, L., Ren, D., et al. (2025) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.70077 · Cited by 4
“8 In addition, previous studies focused mainly on PA volume (e.g., steps per day) and/or intensity (e.g., moderate to vigorous PA [MVPA]), 5,6,8 which may underestimate the true association between PA and cognition in older adults with slower speeds of movement and lower aerobic capacity.”
Cai, Y., Snitz, B. E., & Cohen, A. D. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71181 · Cited by 1
“7,8 11 Studiesusingaccelerometerassessmentshavemainlyfocusedonsum-mary measures (e.g., steps/day, moderate to vigorous PA), 6,10,11 which may underestimate associations due to measurement error and mis-classification by using cutpoints.”
Feter, N., Nanda, A., Hourihan, S., Aslan, D. H., Feter, J. S., Sayre, M. K., Bharadwaj, P. K., Ally, M., Song, H., Arora, A., et al. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71582 · Cited by 1
Amyloid-beta relates to default and attention network connectivity during working memory retrieval
He, H., Habeck, C. G., & Stern, Y. (2026) · Brain Communications · doi:10.1093/braincomms/fcag278 · Cited by 1
“PA is one potential modifiable factor for reducing the risk of cognitive decline and dementia 12,73 ; however, pathways underlying its contribution of resilience against developing dementia are unknown.”
Is Alzhezimer’s disease a New Type Diabetes? Crosstalk between two serious disorders: review
Dobosz, M., Rudziński, G., Chilimoniuk, Z., Więsyk, P. J., Kusak, N., & Chałupnik, A. (2023) · Journal of Education Health and Sport · doi:10.12775/jehs.2023.13.03.017 · Cited by 2
Cognitive Benefits of Physical Activity in the Elderly: A Narrative Review
Ghosh, A., Jagtap, T., & Issac, T. G. (2023) · Journal of Psychiatry Spectrum · doi:10.4103/jopsys.jopsys_40_23 · Cited by 1
Heinze, T., Tuchtenhagen, M., Knüppel, S., Weber, D., Pohl, G., Jannasch, F., Schiborn, C., Schulze, M. B., Grune, T., & Schwerdtle, T. (2025) · Journal of Alzheimer s Disease · doi:10.1177/13872877251333726 · Cited by 1
“3,8 Therefore, results from the present univariate comparisons, especially in the groups below the age of 50 should be viewed with caution as they contained only 4 to 15 individuals, requiring a larger sample size for con fi rmation.”
Rolland, Y., & Barreto, P. D. S. (2022) · Wiley eBooks · doi:10.1002/9781119484288.ch67 · Cited by 1
Wawrzyniak, A. J. (2020) · Springer eBooks · doi:10.1007/978-3-030-39903-0_803 · Cited by 1
Asociaciones entre dieta y función cognitiva en el Proyecto SUN
Muñoz, M. I. (2022) · Deposito Adademico Digital Universidad De Navarra (University of Navarra) · doi:10.15581/10171/63292 · Cited by 1
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. (2023) · medRxiv · doi:10.1101/2023.05.15.23289982 · Cited by 1
Porto, F. H. D. G. (2017) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.5.2017.tde-27102017-100935
Diesfeldt, H. (2018) · Denkbeeld · doi:10.1007/s12428-018-0023-z
Hurley, D. (2018) · Neurology Today · doi:10.1097/01.nt.0000542312.76422.dc
Nutrition and Exercise Approaches to Enhance Muscle, Mobility, and Cognition During Aging
Daly, R. M., Formica, M., Tait, J. L., & Macpherson, H. (2018) · Springer eBooks · doi:10.1007/978-3-319-98464-3_8
Risk factors for development of neurocognitive disorders
Gustavsson, A. (2019) · Lund University Publications (Lund University)
Epigenetic Modifications lead towards Neurodegeneration
Askari, A., Noushad, S., Ahmed, S., Mirza, F., & Aziz, S. A. (2020) · INTERNATIONAL JOURNAL OF ENDORSING HEALTH SCIENCE RESEARCH (IJEHSR) · doi:10.29052/jehsr.v8.i2.2020.86-108
La physiothérapie pour un vieillissement en bonne santé
Liu-Ambrose, T. Y. L., & LI, L. C. (2022) · Physiotherapy Canada · doi:10.3138/ptc-2021-0106-gef
Körperliche Aktivität und sportliche Bewegung bei Demenz
Ngamsri, T., Claussen, M. C., & Hemmeter, U. (2019) · Swiss Sports & Exercise Medicine · doi:10.34045/ssem/2019/31
“Mehrere Studien zeigen, dass körperliche Aktivität zur Prävention von Demenzerkrankungen eingesetzt werden kann, indem der kognitive Abbau und das Eintreten einer AD verzögert wird [5,6].”
BackgroundPhysicial activity, sedentary behaviour and markers of cardiovascular and brain diseases
Vandercappellen, E. J. (2023) · doi:10.26481/dis.20230703ev
Successful Maintenance of Brain Sharpness
Demarin, V., & Đerke, F. (2023) · Springer eBooks · doi:10.1007/978-3-031-33013-1_11
Takács, J., Járai, D., & Koller, Á. (2024) · Developments in Health Sciences · doi:10.1556/2066.2024.00060
The global dementia pandemic in the elderly
Karadinović, M., Mladenović, D., Pokimica, S., Ilić, S., Erić, R., Veljović, M., Joković, S., Marković, M., & Andrić, D. (2024) · Glasnik javnog zdravlja · doi:10.5937/serbjph2403210k
Healthy lifestyles, plasma proteomic profile and long-term risk of dementiaPreprint
Shen, J., Wu, M., Huang, Y., Yan, M., Yang, Y., Xu, X., Zong, G., Yang, J., Li, X., Chen, H., et al. (2024) · medRxiv · doi:10.1101/2024.12.01.24317800
Metadata
- 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
- 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
- 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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