Network‐based Plasma Proteomics Reveals Molecular Overlap Between Physical Activity and Dementia Risk

Abstract

Physical activity (PA) is linked to lower dementia risk, but molecular pathways underpinning PA-related dementia risk are poorly understood. We conducted plasma proteomics (SomaScan v4.1) and 30-day Fitbit-based PA monitoring (average daily step count) in 65 cognitively unimpaired older adults from the UCSF BrANCH cohort. Differential regression and network analyses identified PA plasma proteomic signatures tied to extracellular matrix (ECM), immune response, and lipid metabolism. Protein module M12 ECM/neurodevelopment positively correlated with PA in BrANCH and external cohorts, inversely predicted cognitive aging outcomes in BrANCH, and decreased across multiple neurodegenerative conditions. M12 was enriched for proteins from Alzheimer’s disease (AD) risk genes and antemortem plasma abundance of ANTXR2, an M12 ‘hub’ protein, forecasted longitudinal cognitive decline and postmortem brain tissue protein signatures of AD cognitive resilience in the ROSMAP cohort. Our integrated analysis across six proteomic datasets identified blood-detectable molecular signatures of PA and neurodegenerative disease, including ECM-related proteins (e.g., ANTXR2) that may represent key molecular targets for dementia prevention. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement National Institutes of Health grant R01AG032289 (JHK) National Institutes of Health grant R01AG048234 (JHK) National Institutes of Health grant P30AG062422 (GDR) National Institutes of Health grant R01AG072475 (KBC) National Institutes of Health grant UF1NS100608 (JHK) National Institutes of Health grant K23AG058752 (KBC) Alzheimers Association Research Grant AARG-20-683875 (KBC) Larry L. Hillblom Foundation grant 2024-A-001-CTR (KBC) Larry L. Hillblom Foundation grant 2018-A-006-NET (JHK) Alzheimers Association grant AARF-23-1145318 (RS) New Vision Research grant CCAD 2024-001-1 (RS) American Academy of Neurology Fellowship Award (RS) Alzheimers Association grant AARF-22-974065 (EWP) National Institutes of Health grant K23AG084883 (EWP) National Institutes of Health grant P30AG062422 (EWP) Shenandoah Foundation (EWP) ALLFTD Consortium grant U19AG063911 (funded by the National Institute on Aging and the National Institute of Neurological Diseases and Stroke) ARTFL Consortium grant U54NS092089 (funded by the National Institute of Neurological Diseases and Stroke and National Center for Advancing Translational Sciences) LEFFTDS Consortium grant U01AG045390 (funded by the National Institute on Aging and the National Institute of Neurological Diseases and Stroke) National Institutes of Health grant P50AG047366 (Stanford ADRC) National Institutes of Health grant P30AG066515 (Stanford ADRC) National Institutes of Health grant P30AG10161 (ROSMAP) National Institutes of Health grant P30AG72975 (ROSMAP) National Institutes of Health grant R01AG15819 (ROSMAP) National Institutes of Health grant R01AG17917 (ROSMAP) National Institutes of Health grant U01AG46152 (ROSMAP) National Institutes of Health grant U01AG61356 (ROSMAP) Gates Ventures (ROSMAP) NIH and HHS Contract nos. 75N92022D00001; 75N92022D00002; 75N92022D00003; 75N92022D00004; 75N92022D00005 (ARIC study) NIHLBI grant R01HL134320 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The University of California, San Francisco Committee on Human Research gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes 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). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes UCSF BrANCH data are available on reasonable request made to the UCSF Memory and Aging Center. Academic, not-for-profit investigators can request data for professional education and for research studies. Requests can be made online (https://memory.ucsf.edu/research-trials/professional/open-science). Datasets used for the analyses for the current study are also available from the corresponding author on reasonable request. Algorithms used for protein data processing and analysis are available in existing R packages and at https://github.com/edammer, as described in the Methods. ROSMAP resources can be requested at https://www.radc.rush.edu and www.synpase.org. Pre-existing data access policies for each of the ARIC parent cohort studies specify that research data requests can be submitted to each steering committee; these will be promptly reviewed for confidentiality or intellectual property restrictions and will not unreasonably be refused. Please refer to the data sharing policies of these studies. Individual level patient or protein data may further be restricted by consent, confidentiality or privacy laws/considerations. These policies apply to both clinical and proteomic data.