Physical activity (PA), including sedentary behavior, is associated with many diseases, including Alzheimers disease and all-cause dementia. However, the specific biological mechanisms through which PA protects against disease are not entirely understood. To address this knowledge gap, we first assessed the conventional observational associations of three self-reported and three device-based PA measures with circulating levels of 2,911 plasma proteins measured in the UK Biobank (nmax=39,160) and assessed functional enrichment of identified proteins. We then used bi-directional Mendelian randomization (MR) to evaluate further the evidence for causal relationships of PA with protein levels. Finally, we performed mediation analyses to identify proteins that may mediate the relationship of PA with incident all-cause dementia. Our findings revealed 41 proteins consistently associated with all PA measures and 1,027 proteins associated with at least one PA measure. Both conventional observational and MR study designs converged on proteins that appear to increase as a result of PA, including integrin proteins such as ITGAV and ITGAM, as well as MXRA8, CLEC4A, CLEC4M, GFRA1, ADGRG2, and PTGDS; and on proteins that appear to decrease as a result of PA such as LEP, LPL, INHBC, CLMP, PTGDS, ADM, OGN, and PI3. Functional enrichment analyses revealed several relevant processes, including cell-matrix adhesion, integrin-mediated signaling, and collagen binding. Finally, several proteins, including GDF15, ITGAV, HPGDS, BCAN, and MENT, were found to mediate the relationship of PA with all-cause dementia, implicating processes such as synaptic plasticity, neurogenesis and inflammation as mechanisms through which PA protects against dementia. Our results provide insights into how PA may affect biological processes and protect from all-cause dementia and provide avenues for future research into the health-promoting effects of PA.

The authors have declared no competing interest.

The authors would also like to acknowledge funding from NIH R01AG072445.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee/IRB of the North West Multi-centre Research Ethics Committee (MREC) waived ethical approval for this work under UK Biobank's Research Tissue Bank (RTB) approval.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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Individual-level data from the UK Biobank can be requested at https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access. Summary statistics for all GWAS used in this study are publicly available from the GWAS catalog (64) and UKB-PPP at https://doi.org/10.7303/syn51364943. Our analysis codes, and results, including interactive visualizations of results, are available in a GitHub repository: https://github.com/klimentidis-lab/ProteomicsofPhysicalActivity2024.git

https://github.com/klimentidis-lab/ProteomicsofPhysicalActivity2024.git