Physical activity as a modifiable risk factor in preclinical Alzheimer’s disease
Physical inactivity is a recognized modifiable risk factor for Alzheimer's disease (AD), yet its relationship with progression of AD pathology in humans remains unclear, limiting the effective translation into prevention trials. Using pedometer-measured step counts in cognitively unimpaired older adults, we demonstrated an association between higher physical activity and slower cognitive and functional decline in individuals with elevated baseline amyloid. Importantly, this beneficial association was not related to lower amyloid burden at baseline or longitudinally. Instead, higher physical activity was associated with slower amyloid-related inferior temporal tau accumulation, which significantly mediated the association with slower cognitive decline. Dose-response analyses further revealed a curvilinear relationship, where the associations with slower tau accumulation and cognitive decline reached a plateau at a moderate level of physical activity (5,001-7,500 steps per day), potentially offering a more approachable goal for older sedentary individuals. Collectively, our findings support targeting physical inactivity as an intervention to modify the trajectory of preclinical AD in future prevention trials, and further suggest that preferentially enrolling sedentary individuals with elevated amyloid may maximize the likelihood of demonstrating a protective effect of physical activity on tau accumulation and cognitive and functional decline in early AD.
Authors
- Reisa Anne Sperling (ORCID: https://orcid.org/0000-0003-1535-6133)
- Aaron P. Schultz (ORCID: https://orcid.org/0000-0002-0418-0999)
- Dylan Kirn
- Zahra Shirzadi (ORCID: https://orcid.org/0000-0001-6854-9356)
- Rachel F. Buckley (ORCID: https://orcid.org/0000-0002-5356-5537)
- Wai‐Ying Wendy Yau (ORCID: https://orcid.org/0000-0002-7597-7647)
- Jennifer S. Rabin (ORCID: https://orcid.org/0000-0003-4754-2221)
- Stephanie A. Schultz (ORCID: https://orcid.org/0000-0001-8460-4415)
- Jeremy J. Pruzin (ORCID: https://orcid.org/0000-0002-0443-4194)
- Dorene M. Rentz (ORCID: https://orcid.org/0000-0002-6318-9213)
- Michael J Properzi (ORCID: https://orcid.org/0000-0001-7855-2372)
- Paulo Matos (ORCID: https://orcid.org/0000-0002-9379-9696)
- Jasmeer P. Chhatwal (ORCID: https://orcid.org/0000-0002-7792-1698)
- Keith A. Johnson (ORCID: https://orcid.org/0000-0002-5916-6043)
- Courtney Maa
- Kailee Palmgren
Institutions
- Sunnybrook Health Science Centre (CA)
- Harvard University (US)
- The University of Melbourne (AU)
- University of Toronto (CA)
- Toronto Rehabilitation Institute (CA)
- Health Sciences Centre (CA)
- Massachusetts General Hospital (US)
- Banner Alzheimer’s Institute
- Sunnybrook Research Institute
- Mass General Brigham (US)
Publication Details
- Journal
- Nature Medicine
- Published
- 2025-11-03
- DOI
- https://doi.org/10.1038/s41591-025-03955-6
- Citations
- 13
- Primary Topic
- Dementia and Cognitive Impairment Research
- Type
- article
- Field-Weighted Citation Impact
- 19.13
Funders
- Massachusetts General Hospital
- Massachusetts Life Sciences Center
- Centre d'Imagerie BioMédicale
- National Institutes of Health
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital
- National Institute of Biomedical Imaging and Bioengineering