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We leveraged large-scale plasma proteomics to identify biological signatures of objectively monitored PA and cognitive ageing in functionally intact older adults, cross-validated these signatures in independent exercise cohorts and tested associations with both symptomatic and presymptomatic stages of neurodegeneration across multiple Alzheimer\u2019s disease and related dementias (ADRD) cohorts. We analysed large-scale plasma proteomics data (SomaScan 7k) across three cohorts including naturalistic, objective PA monitoring (University of California, San Francisco Brain Aging Network for Cognitive Health cohort, n = 65), self-reported PA (Atherosclerosis Risk In Communities study, n = 10 644) and PA intervention (Health Risk Factors, Exercise Training and Genetics study, n = 654). Differential regression models examined individual protein correlates of PA, adjusting for age and sex. Weighted gene co-expression network analysis assembled proteins into unbiased modules of protein co-expression, which were annotated for gene ontology and cell-type enrichment. To test clinical relevance to ADRD, we examined PA-related protein levels across-cohorts of symptomatic Alzheimer\u2019s disease and Parkinson\u2019s disease (Stanford Alzheimer\u2019s Disease Research Center), as well as frontotemporal dementia-spectrum disorders (ARTFL\/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium). PA-related plasma proteins were also tested as predictors of antemortem cognitive change and post-mortem brain tissue mass spectrometry proteomic signatures in brain donors from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) cohort. Differential regression and network analyses identified PA plasma proteomic signatures linked to cell adhesion\/extracellular matrix (ECM), immune response and lipid metabolism. Protein co-expression module M12 ECM\/neurodevelopment harboured growth factor, cell adhesion and vascular remodelling proteins that (i) were positively associated with PA across exercise cohorts, (ii) positively associated with cognitive function and (iii) negatively associated with Alzheimer\u2019s disease, Parkinson\u2019s disease and frontotemporal dementia. Furthermore, M12 was enriched for proteins from Alzheimer\u2019s disease risk genes and antemortem plasma abundance of anthrax toxin receptor cell adhesion molecule 2 (ANTXR2), an M12 \u2018hub\u2019 protein and top PA hit across-cohorts, forecasted longitudinal global cognitive decline and post-mortem brain tissue signatures of synaptic function and proteolysis in ROSMAP. Collectively, our integrated systems biology analysis of six independent plasma proteomic datasets facilitated discovery and validation of blood-detectable molecular signatures of PA and neurodegenerative disease, including PA-related proteins with clinical and biological relevance to early stages of disease. Circulating levels of PA-related proteins reflecting ECM biology (e.g. ANTXR2) may represent key molecular targets for dementia prevention.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag287","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:21:17Z","timestamp":1784546477000},"source":"Crossref","is-referenced-by-count":0,"title":["Plasma proteomics reveals molecular overlap between physical activity and dementia risk"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1351-6183","authenticated-orcid":false,"given":"Rowan","family":"Saloner","sequence":"first","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco , San Francisco, CA 94158 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily W","family":"Paolillo","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco , San Francisco, CA 94158 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M","family":"VandeBunte","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco , San Francisco, CA 94158 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire J","family":"Cadwallader","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco , San Francisco, CA 94158 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coty","family":"Chen","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco , San Francisco, CA 94158 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian T","family":"Steffen","sequence":"additional","affiliation":[{"name":"Division of Computational Health Sciences, Department of Surgery, University of Minnesota , Minneapolis, MN 55455 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3689-554X","authenticated-orcid":false,"given":"David A","family":"Bennett","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center, Rush University Medical Center , Chicago, IL 60612 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4153-8187","authenticated-orcid":false,"given":"Bradley F","family":"Boeve","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard J","family":"Rosen","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco , San Francisco, CA 94158 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam L","family":"Boxer","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco , San Francisco, CA 94158 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel H","family":"Kramer","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco , San Francisco, CA 94158 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