Plasma proteomics reveals molecular overlap between physical activity and dementia risk

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ID: 321802
2026
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Abstract
Abstract Physical activity (PA) is a modifiable lifestyle behavior associated with lower dementia risk; however, molecular pathways bridging PA-related dementia prevention are poorly understood. We leveraged large-scale plasma proteomics to identify biological signatures of objectively-monitored PA and cognitive aging 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’s disease (AD) and related dementias (ADRD) cohorts. We analyzed 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 AD and Parkinson’s disease (PD; Stanford Alzheimer’s Disease Research Center), as well as frontotemporal dementia (FTD)-spectrum disorders (ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium). PA-related plasma proteins were also tested as predictors of antemortem cognitive change and postmortem 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 harbored growth factor, cell adhesion, and vascular remodeling proteins that 1) were positively associated with PA across exercise cohorts, 2) positively associated with cognitive function, and 3) negatively associated with AD, PD, and FTD. Furthermore, M12 was enriched for proteins from AD risk genes and antemortem plasma abundance of anthrax toxin receptor cell adhesion molecule 2 (ANTXR2), an M12 ‘hub’ protein and top PA hit across cohorts, forecasted longitudinal global cognitive decline and postmortem brain tissue signatures of synaptic function and proteolysis in ROSMAP. Collectively, our integrated systems biology analysis of 6 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.
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Authors Rowan Saloner, Emily W. Paolillo, Anna M. VandeBunte, Claire J. Cadwallader, Coty Chen, Brian T. Steffen, David A. Bennett, Bradley F. Boeve, Howard J. Rosen, Adam L Boxer, Joel H Kramer, Vahan Aslanyan
Journal Brain communications
Year 2026
DOI
10.1093/braincomms/fcag287
URL
https://doi.org/10.1093/braincomms/fcag287
Keywords Keywords not found

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