Late‐life physical activity relates to brain tissue synaptic integrity markers in older adults
Open accessAbstract
Introduction: Physical activity (PA) is widely recommended for age‐related brain health, yet its neurobiology is not well understood. Animal models indicate PA is synaptogenic. We examined the relationship between PA and synaptic integrity markers in older adults. Methods: Four hundred four decedents from the Rush Memory and Aging Project completed annual actigraphy monitoring (Mean visits = 3.5±2.4) and post mortem evaluation. Brain tissue was analyzed for presynaptic proteins (synaptophysin, synaptotagmin‐1, vesicle‐associated membrane proteins, syntaxin, complexin‐I, and complexin‐II), and neuropathology. Models examined relationships between late‐life PA (averaged across visits), and timing‐specific PA (time to autopsy) with synaptic proteins. Results: Greater late‐life PA associated with higher presynaptic protein levels (0.14 < β < 0.20), except complexin‐II (β = 0.08). Relationships were independent of pathology but timing specific; participants who completed actigraphy within 2 years of brain tissue measurements showed largest PA‐to‐synaptic protein associations (0.32 < β < 0.38). Relationships between PA and presynaptic proteins were comparable across brain regions sampled. Discussion: PA associates with synaptic integrity in a regionally global, but time‐linked nature in older adults.
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Physical activity appears to decrease risk of dementia.
“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 [128]
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“12,24,27,28 Functionalvesicularneurotrans-missionrequirestheformationofaSNARE(solubleN-ethylmaleimide-sensitive factor attachment protein receptor) protein complex, comprised of syntaxin-1 (STX1), synaptosome-associated protein 25 (SNAP25), and vesicle-associated membrane protein (VAMP or…”
Self-citationThe behavioural effect of short-term cognitive and physical intervention therapies in old dogs
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“Future studies should investigate whether physical interventions influence the structure of brain tissue, similarly to how they do in humans [49].”
BackgroundDemand Coupling Drives Neurodegeneration: A Model of Age-Related Cognitive Decline and Dementia
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Effect of exercise engagement and cardiovascular risk on neuronal injury
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“8 17 A few observational studies have found associations with exercise for SNAP-25 and NfL in plasma and brain tissue, 18–20 while one study failed to find an association.”
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“found physical activity provides a powerful neuroprotective factor even in light of existing neuropathologies (36).”
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“However, physical fitness may have potentially increased the participants resilience (Casaletto et al., 2022) by protecting EF through neurobiological mechanisms.”
Lifestyle Factors and Successful Cognitive Aging in Older Adults
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“These associations are partly mediated by structural brain changes, such as slower gray matter atrophy [11], maintained white matter integrity [44], and enhanced synaptic connectivity [45].”
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“This was unexpected, as both physical activity and mindful relaxation are reportedly associated with both enhanced cognitive function and reduced levels of stress (Casaletto et al., 2022; Lazar et al., 2000).”
Physical activity interventions in cognitive aging
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“On the other hand, the positive effects from exercise were not really lasting 26 .”
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“For instance, a postmortem cohort study demonstrated that individuals with higher late-life PA levels displayed elevated expression of multiple synaptic markers in brain tissue, including synaptophysin, vesicle-associated membrane protein, SNAP25, synaptotagmin-1, and syntaxin [29].”
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“13 18 In 2025, Chen et al proposed a wearable-derived daily HR per step (DHRPS) metric that incorporated HR with daily activity in relation to cardiovascular disease (CVD) factors.”
Schwarck, S., Behrenbruch, N., Schumann‐Werner, B., Molloy, E. N., Garcia‐Garcia, B., Hochkeppler, A., Fischer, L., Büchel, A., Incesoy, E. I., Bernal, J., et al. (2026) · npj Aging · doi:10.1038/s41514-026-00512-4
“Together, these fi ndings suggest that the role of physical fi tness in cognitive resilience to tau pathology remains uncertain 41 – 44 Exercise is thought to promote cognitive health through molecular pathways involved in neuroplasticity.”
- Authors
- Casaletto, K., Ramos‐Miguel, A., VandeBunte, A., Memel, M., Buchman, A., Bennett, D., & Honer, W.
- Affiliations
- University of California, San Francisco (US)
- University of the Basque Country (ES)
- San Francisco VA Medical Center (US)
- Rush University Medical Center (US)
- University of British Columbia (CA)
- Corresponding author
- Casaletto, Kaitlin
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2022-01-07
- Volume
- 18
- Issue
- 11
- Pages
- 2023-2035
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC9259753
- OpenAlex
- W4205928060
- Cited by
- 53
- References
- 51
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 16 · 2023: 9 · 2022: 9 · 2021: 1
- FWCI
- 6.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Alzheimer s & Dementia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG017917, K23AG058752, R01AG072475)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Physical Activity and Health
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- physical activity, synaptic integrity
- MeSH terms
- Aging, Animals, Brain, Exercise, Actigraphy
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