| Title: | Plasma Proteomic Signatures of Physical Activity Provide Insights into Biological Impacts and its Protective Role against Dementia |
| Journal: | Medicine & Science in Sports & Exercise |
| Published: | 26 Jan 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41582318/ |
| DOI: | https://doi.org/10.1249/mss.0000000000003948 |
Publication 18467
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Abstract
PURPOSE: Physical activity (PA) and sedentary behavior (SB) are associated with many diseases, including Alzheimer's disease and all-cause dementia. However, the specific biological mechanisms through which PA protects against disease are not entirely understood. This study aims to address this gap, with a specific focus on all-cause dementia.</p>
METHODS: We first assessed the conventional observational associations of three self-reported and three device-based PA/SB measures with circulating levels of 2,911 plasma proteins measured in the UK Biobank (n max =39,160) and assessed functional enrichment of identified proteins. We then used bi-directional Mendelian randomization (MR) to further evaluate the evidence for causal relationships of PA/SB with protein levels. Finally, we performed mediation analyses to identify proteins that may mediate the relationship of PA with incident all-cause dementia.</p>
RESULTS: 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 integrins such as ITGAV and ITGAM, as well as MXRA8, CLEC4A, CLEC4M, LPL, and ADGRG2; on proteins that appear to decrease as a result of PA such as LEP, INHBC, CLMP, PTGDS, ADM, OGN, and PI3; and on proteins that are more responsive to high-intensity PA, such as CA14, CA6, CA4, KIT, and ANGPT2. Functional enrichment analyses revealed processes such as cell-matrix adhesion, integrin-mediated signaling, and collagen binding. Finally, GDF15, ITGAV, ITGAM, ITGA11, HPGDS, GFAP, ADM, AHNAK, and DPP4 were among 21 unique proteins found to mediate the relationship of PA with all-cause dementia, implicating processes such as synaptic plasticity, neurogenesis, and inflammation.</p>
CONCLUSIONS: Our results provide insights into how PA affects biological processes and protects against dementia, and provide avenues for future research into the health-promoting effects of PA.</p>
24 Authors
- Gayatri Arani
- Amit Arora
- Shuai Yang
- Jingyue Wu
- Jennifer N Kraszewski
- Amy Martins
- Alexandra Miller
- Zebunnesa Zeba
- Ayan Jafri
- Chengcheng Hu
- Leslie V Farland
- Jennifer W Bea
- Dawn K Coletta
- Daniel H Aslan
- M Katherine Sayre
- Pradyumna K Bharadwaj
- Madeline Ally
- Silvio Maltagliati
- Mark H C Lai
- Rand Wilcox
- Eco de Geus
- Gene E Alexander
- David A Raichlen
- Yann C Klimentidis
1 Application
| Application ID | Title |
|---|---|
| 21259 | The genetic basis for Alzheimer?s and neurodegenerative disease ? understanding etiology and interaction with other risk factors. |
Enabling scientific discoveries that improve human health