Research Paper Volume 14, Issue 23 pp 9423—9444

DNA methylation-based measures of biological aging and cognitive decline over 16-years: preliminary longitudinal findings in midlife

Rebecca G. Reed1, , Judith E. Carroll2, , Anna L. Marsland1, , Stephen B. Manuck1, ,

  • 1 Department of Psychology, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA
  • 2 Cousins Center for Psychoneuroimmunology, Department of Psychiatry and Biobehavioral Science, Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA

Received: July 8, 2022       Accepted: October 29, 2022       Published: November 11, 2022
How to Cite

Copyright: © 2022 Reed et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


DNA methylation-based (DNAm) measures of biological aging associate with increased risk of morbidity and mortality, but their links with cognitive decline are less established. This study examined changes over a 16-year interval in epigenetic clocks (the traditional and principal components [PC]-based Horvath, Hannum, PhenoAge, GrimAge) and pace of aging measures (Dunedin PoAm, Dunedin PACE) in 48 midlife adults enrolled in the longitudinal arm of the Adult Health and Behavior project (56% Female, baseline AgeM = 44.7 years), selected for discrepant cognitive trajectories. Cognitive Decliners (N = 24) were selected based on declines in a composite score derived from neuropsychological tests and matched with participants who did not show any decline, Maintainers (N = 24). Multilevel models with repeated DNAm measures within person tested the main effects of time, group, and group by time interactions. DNAm measures significantly increased over time generally consistent with elapsed time between study visits. There were also group differences: overall, Cognitive Decliners had an older PC-GrimAge and faster pace of aging (Dunedin PoAm, Dunedin PACE) than Cognitive Maintainers. There were no significant group by time interactions, suggesting accelerated epigenetic aging in Decliners remained constant over time. Older PC-GrimAge and faster pace of aging may be particularly sensitive to cognitive decline in midlife.


AHAB: Adult Health and Behavior; CI: confidence interval; DNAm: DNA methylation; PACE: pace of aging calculated from the epigenome; PC: principal component; PoAm: pace of aging from methylation; T: time; WAIS: Wechsler Adult Intelligence Scale.