DNA methylation age from peripheral blood predicts progression to Alzheimer’s disease, white matter disease burden, and cortical atrophy
Cross-sectional studies suggest a limited relationship between accelerated epigenetic aging derived from epigenetic clocks, and Alzheimer's disease (AD) pathophysiology or risk. However, most prior analyses have not utilized longitudinal analyses or whole-brain neuroimaging biomarkers of AD. Herein, we employed longitudinal modeling and structural neuroimaging analyses to test the hypothesis that accelerated epigenetic aging would predict AD progression. Using survival analyses, we found that two second-generation epigenetic clocks, DNAmPhenoAge and DNAmGrimAge, predicted progression from cognitively normal aging to mild cognitive impairment or AD and worse longitudinal cognitive outcomes. Epigenetic age was also strongly associated with cortical thinning in AD-relevant regions and white matter disease burden. Thus, in contrast to earlier work suggesting limited applicability of blood-based epigenetic clocks in AD, our novel analytic framework suggests that second-generation epigenetic clocks have broad utility and may represent promising predictors of AD risk and pathophysiology.
Authors
- Agustín M. Ibáñez (ORCID: https://orcid.org/0000-0001-6758-5101)
- Alina P.S. Pang (ORCID: https://orcid.org/0000-0001-6677-7355)
- Hernando A Santamaría‐García (ORCID: https://orcid.org/0000-0001-9422-3579)
- Bruce L. Miller (ORCID: https://orcid.org/0000-0002-2152-4220)
- Luke W. Bonham (ORCID: https://orcid.org/0000-0002-2533-1266)
- Leo P. Sugrue (ORCID: https://orcid.org/0000-0001-7315-4519)
- Jennifer S. Yokoyama (ORCID: https://orcid.org/0000-0001-7274-2634)
- Daniel W. Sirkis (ORCID: https://orcid.org/0000-0003-3440-8859)
- Michael J. Corley (ORCID: https://orcid.org/0000-0001-8957-7153)
Institutions
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- University of California, San Francisco (US)
- Cornell University (US)
- Adolfo Ibáñez University (CL)
- Pontificia Universidad Javeriana (CO)
- University of San Andrés (AR)
- Centro Científico Tecnológico - San Juan (AR)
- Hospital Universitario San Ignacio (CO)
- Global Brain Health Institute (US)
- Weill Cornell Medicine (US)
Publication Details
- Journal
- npj Dementia
- Published
- 2025-05-27
- DOI
- https://doi.org/10.1038/s44400-025-00007-1
- Citations
- 9
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 7.25
Funders
- Alzheimer's Association
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- Biogen
- RSNA Research and Education Foundation
- University of Southern California
- Radiological Society of North America
- Meso Scale Diagnostics
- Alzheimer's Disease Neuroimaging Initiative
- BioClinica
- Novartis Pharmaceuticals Corporation
- Northern California Institute for Research and Education
- Global Brain Health Institute
- Rainwater Charitable Foundation
- Eisai
- Servier
- H. Lundbeck A/S
- IXICO
- Agencia Nacional de Investigación y Desarrollo
- National Institutes of Health
- Genentech
- Canadian Institutes of Health Research
- National Institute on Aging
- National Institute on Drug Abuse
- Fogarty International Center
- National Institute of Neurological Disorders and Stroke
- National Institute of Biomedical Imaging and Bioengineering
- Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias