Association of a pace of aging epigenetic clock with rate of cognitive decline in the Framingham Heart Study Offspring Cohort

Micah J Savin; Haoyang Wang; Heming Pei; Allison E Aiello; Stephanie Assuras; Avshalom Caspi; Terrie E Moffitt; Peter A Muenning; Calen P Ryan; Baoyi Shi; Yaakov Stern; Karen Sugden; Linda Valeri; Daniel W Belsky

doi:10.1002/dad2.70038

Association of a pace of aging epigenetic clock with rate of cognitive decline in the Framingham Heart Study Offspring Cohort

Alzheimers Dement (Amst). 2024 Nov 23;16(4):e70038. doi: 10.1002/dad2.70038. eCollection 2024 Oct-Dec.

Authors

Micah J Savin¹, Haoyang Wang^{1

2}, Heming Pei^{1

3}, Allison E Aiello^{1

3}, Stephanie Assuras⁴, Avshalom Caspi^{5

6

7

8}, Terrie E Moffitt^{5

6

7

8}, Peter A Muenning⁹, Calen P Ryan¹, Baoyi Shi², Yaakov Stern^{10

11

12}, Karen Sugden^{5

6}, Linda Valeri^{2

3}, Daniel W Belsky^{1

3}

Affiliations

¹ Robert N. Butler Columbia Aging Center Mailman School of Public Health Columbia University Irving Medical Center New York New York USA.
² Department of Biostatistics MSPH Columbia University Irving Medical Center New York New York USA.
³ Department of Epidemiology MSPH Columbia University Irving Medical Center New York New York USA.
⁴ Neuropsychology Department of Neurology Columbia University Irving Medical Center New York New York USA.
⁵ Department of Psychology & Neuroscience Trinity College of Arts & Sciences Duke University Durham North Carolina USA.
⁶ Department of Psychiatry and Behavioral Sciences Duke University School of Medicine Durham USA.
⁷ PROMENTA University of Oslo Oslo Norway Problemveien 11 Oslo Norway.
⁸ Social Genetic & Developmental Psychiatry Centre Institute of Psychiatry Psychology & Neuroscience King's College London London United Kingdom 16 De Crespigny Park London UK.
⁹ Health Policy and Management Mailman School of Public Health Columbia University Irving Medical Center New York New York USA.
¹⁰ GH Sergievsky Center Department of Neurology Columbia University Irving Medical Center New York New York USA.
¹¹ Taub Institute Department of Neurology Columbia University Irving Medical Center New York New York USA.
¹² Cognitive Neuroscience Division Department of Neurology Columbia University Medical Center New York New York USA.

Abstract

Introduction: The geroscience hypothesis proposes systemic biological aging is a root cause of cognitive decline.

Methods: We analyzed Framingham Heart Study Offspring Cohort data (n = 2296; 46% male; baseline age M = 62, SD = 9, range = 25-101 y). We measured cognitive decline across two decades of neuropsychological-testing follow-up. We measured pace of aging using the DunedinPACE epigenetic clock. Analysis tested if participants with faster DunedinPACE values experienced more rapid cognitive decline compared with those with slower DunedinPACE values.

Results: Participants with faster DunedinPACE had poorer cognitive functioning at baseline and experienced more rapid cognitive decline over follow-up. Results were robust to confounders and consistent across population strata. Findings were similar for the PhenoAge and GrimAge epigenetic clocks.

Discussion: Faster pace of aging is a risk factor for preclinical cognitive decline. Metrics of biological aging may inform risk stratification in clinical trials and prognosis in patient care.

Highlights: Faster DunedinPACE is associated with preclinical cognitive aging.Higher baseline cognition was protective of DunedinPACE-associated cognitive decline.The DunedinPACE association with cognitive decline explained a fourth of dementia risk.

Keywords: Alzheimer's disease and related dementias; DunedinPACE; aging; biological aging; cognitive decline; epigenetic clocks.