Epigenetic age acceleration and midlife cognition: joint evidence from observational study and Mendelian randomization

Yang Pan; Zhijie Huang; Xiao Sun; Ileana De Anda-Duran; Ruiyuan Zhang; Wei Chen; Changwei Li; Ana W Capuano; Kristine Yaffe; Jinying Zhao; David A Bennett; Owen T Carmichael; Lydia A Bazzano; Tanika N Kelly

doi:10.1038/s41514-025-00265-6

Epigenetic age acceleration and midlife cognition: joint evidence from observational study and Mendelian randomization

NPJ Aging. 2025 Aug 18;11(1):75. doi: 10.1038/s41514-025-00265-6.

Authors

Affiliations

¹ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, College of Medicine, University of Illinois Chicago, Chicago, IL, USA.
² Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.
³ Peter O'Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, USA.
⁴ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁵ Department of Psychiatry and Behavioral Sciences, Neurology, and Epidemiology, University of California, San Francisco, San Francisco, CA, USA.
⁶ Department of Epidemiology, College of Public Health and Health Professions and College of Medicine, University of Florida, Gainesville, FL, USA.
⁷ Pennington Biomedical Research Center, Baton Rouge, LA, USA.
⁸ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, College of Medicine, University of Illinois Chicago, Chicago, IL, USA. tkelly5@uic.edu.

^# Contributed equally.

Abstract

The relationship between epigenetic age acceleration (EAA) and midlife cognitive function remains unclear, with limited causal evidence. We investigated this association in 1252 Black and White middle-aged adults from the Bogalusa Heart Study (BHS) and conducted a two-sample Mendelian randomization (MR) analysis using GWAS summary statistics for EAA (N = 34,710) and cognition (N ≤ 106,162). In BHS, higher Hannum age acceleration, PhenoAge acceleration, and GrimAge acceleration (GrimAA) were each associated with slower processing speed (p < 0.05). Additionally, GrimAA was linked to lower global cognition scores (p < 0.001), independent of covariates. MR analysis suggested a potential link, showing that genetically predicted GrimAA was nominally associated with slower processing speed (p = 0.05). These findings suggest that epigenetic aging, particularly GrimAA, is independently associated with lower cognitive function in midlife and may play an important role in cognitive impairment, especially in processing speed.

Abstract

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