Aging
Navigate
Research Paper|Volume 18|pp 303—326

Association of epigenetic age acceleration with MRI biomarkers of aging and Alzheimer’s disease neurodegeneration

Linda K. McEvoy1, Bowei Zhang2, Steve Nguyen2, Adam X. Maihofer3,4, Caroline M. Nievergelt3,4, Ramon Casanova5, Steve Horvath6, Ake T. Lu7, Christos Davatzikos8, Guray Erus8, Susan M. Resnick8,9, Mark A. Espeland10, Steve Rapp11, Kenneth Beckman12, Luigi Ferrucci13, Andrea Z. LaCroix2, Aladdin H. Shadyab2,14
  • 1Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101, USA
  • 2Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA 92037, USA
  • 3Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
  • 4Veterans Affairs San Diego Healthcare System, Research Service, San Diego, CA 92161, USA
  • 5Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
  • 6Altos Labs Cambridge Institute of Science, Cambridge, UK
  • 7Altos Labs, San Diego, CA 92121, USA
  • 8Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
  • 9Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
  • 10Division of Gerontology and Geriatric Medicine, School of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
  • 11Department of Psychiatry and Behavioral Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27103, USA
  • 12Genomics Center, University of Minnesota, Minneapolis, MN 55455, USA
  • 13Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21225, USA
  • 14Division of Geriatrics, Gerontology, and Palliative Care, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
Received: January 1, 2026Accepted: March 11, 2026Published: April 7, 2026

Copyright: © 2026 McEvoy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Epigenetic clocks of biological aging have been associated with cognitive impairment and dementia. Less is known about whether they are associated with an older-appearing brain or with an atrophy pattern associated with dementia. We examined associations of five epigenetic clocks measured at baseline with the Spatial Pattern of Atrophy for Recognition of Brain Aging (SPARE-BA) and the Alzheimer’s Disease Pattern Similarity Score (AD-PS) derived from structural MRIs obtained an average of 8 years later among 1,196 older women. Using linear regression models adjusting for relevant covariates, we observed no associations between any epigenetic clock and accelerated brain aging based on SPARE-BA. We observed a significant association between AgeAccelGrim2 and AD-PS (β = 0.015; 95% CI 0.004 to 0.027; p = 0.01). This association appeared to be primarily driven by the association of a DNA methylation marker of smoking pack years with frontal and temporal lobe volumes. AgeAccelGrim2 was not associated with volumes in regions implicated in early AD (hippocampus and entorhinal cortex). Taken together with prior findings, these results suggest that measures of epigenetic and brain age acceleration capture different aspects of biological aging, and that AgeAccelGrim2 is predictive of neurodegenerative changes associated with smoking that increase risk of dementia.