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Basic Science and Pathogenesis
Jaclyn M Eissman1,2, Min N Qiao1,2, Vrinda Kalia3
1The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
Summary
Biological age, measured by epigenetic clocks, predicts Alzheimer's disease (AD) pathology. This finding aids in stratifying AD risk, especially in early stages, by identifying key plasma biomarkers.
Area of Science:
- Gerontology
- Neuroscience
- Epigenetics
Background:
- Advancing chronological age is a primary risk factor for Alzheimer's disease (AD).
- Individual aging trajectories vary, necessitating novel biomarkers for risk stratification, particularly in preclinical AD.
- Epigenetic clocks, assessing biological age via DNA methylation, offer a potential tool for this stratification.
Purpose of the Study:
- To compute epigenetic clocks (biological age) and assess their association with dementia and AD biomarkers.
- To investigate the correlation between biological age and chronological age, and with sex.
- To validate these correlations in independent cohorts and brain tissue.
Main Methods:
- Utilized whole blood and brain DNA methylation data from the EFIGA cohort (N=731).
- Computed Horvath and Hannum epigenetic clocks and calculated age acceleration.
- Employed linear regression models to test associations between biological age/age acceleration and plasma dementia/AD biomarkers, adjusting for multiple comparisons (FDR).
Main Results:
- Biological age significantly correlated with chronological age and sex in both blood and brain data.
- Replicated correlations in an independent cohort (ROS/MAP).
- Seven plasma biomarkers, including p-tau217, p-tau181, GFAP, p-tau231, NfL, Aβ40, and total-tau, were significantly associated with biological age.
Conclusions:
- Biological age is a significant predictor of Alzheimer's disease pathology across preclinical and clinical stages.
- Future research will evaluate age acceleration as a pathology predictor and validate biomarker associations with autopsy-confirmed neuropathology.
- Investigating sex and APOE-ε4 carrier status stratification will further elucidate AD biomarker relationships.
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