Research Paper|Volume 17, Issue 7|pp 1721—1745

Association of DNA methylation age acceleration with digital clock drawing test performance: the Framingham Heart Study

Zexu Li¹, Huitong Ding^1,², Mengyao Wang³, Yi Li³, Ting Fang Alvin Ang^1,^2,⁴, Gurnani Ashita¹, Katherine A. Gifford¹, Cody Karjadi², Daniel Levy^2,⁵, Rhoda Au^1,^2,^4,^6,^7,⁸, Chunyu Liu^2,³

¹Department of Anatomy and Neurobiology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA
²Framingham Heart Study, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA
³Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA
⁴Slone Epidemiology Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA
⁵Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
⁶Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA
⁷Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA
⁸Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA

Received: January 13, 2025Accepted: June 23, 2025Published: July 21, 2025

https://doi.org/10.18632/aging.206285

Copyright: © 2025 Li 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

Background: The relationship between cognitive function, measured by digital Clock Drawing Test (dCDT), and biological aging is lacking.

Methods: We used linear mixed regression to evaluate the associations between epigenetic aging metrics (Horvath, Hannum, GrimAge, PhenoAge, DunedinPACE) and dCDT scores in the Framingham Heart Study (FHS), adjusting for covariates. Significance was set at a false discovery rate (FDR) <0.05.

Results: Among the 1,789 FHS participants (mean age 65 ± 13, 53% women), higher epigenetic age acceleration metrics at baseline predicted lower dCDT scores approximately seven years later. The magnitude of these associations was greater in older participants (≥65 years, n = 985). The strongest association was observed between the dCDT total score and DunedinPACE in the full sample (beta = −2.1, FDR = 0.0004), the younger (<65 years; beta = −1.9, FDR = 0.02), and older (beta = −2.2, FDR = 0.01) age groups. Additionally, the dCDT total score was associated with age acceleration estimated by Horvath (beta = −1.9, FDR = 0.01) and PhenoAge (beta = −2.5, FDR = 0.01) in older participants, while not in the full sample or younger participants. Furthermore, higher levels of DNAm-based PAI1 (beta = −0.9, FDR = 0.005) and ADM (beta = −2.9, FDR = 0.01), components of GrimAge, were significantly associated with lower dCDT total scores. In analyses of cognitive subdomains, simple motor function was significantly associated with DunedinPACE (FDR = 0.005) in both age groups, and with GrimAge (FDR = 0.05) in the older age group, suggesting that deterioration in various organ systems may particularly impact this domain.

Conclusion: Our findings suggest that advanced biological aging, particularly as captured by DunedinPACE and GrimAge components, is significantly associated with poorer cognitive performance measured by dCDT, especially in older adults, highlighting a potential link between systemic aging processes and cognitive decline.