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Bidirectional relationship between epigenetic age and stroke, dementia, and late-life depression

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  • Cyprien A. Rivier

    (Yale School of Medicine
    Yale Center for Brain and Mind Health)

  • Natalia Szejko

    (Medical University of Warsaw
    University of Calgary)

  • Daniela Renedo

    (Yale School of Medicine
    Yale Center for Brain and Mind Health)

  • Santiago Clocchiatti-Tuozzo

    (Yale School of Medicine
    Yale Center for Brain and Mind Health)

  • Shufan Huo

    (Yale School of Medicine
    Yale Center for Brain and Mind Health)

  • Adam Havenon

    (Yale School of Medicine
    Yale Center for Brain and Mind Health)

  • Hongyu Zhao

    (Yale School of Public Health
    Yale University)

  • Thomas M. Gill

    (Yale School of Medicine)

  • Kevin N. Sheth

    (Yale School of Medicine
    Yale Center for Brain and Mind Health
    Yale School of Medicine)

  • Guido J. Falcone

    (Yale School of Medicine
    Yale Center for Brain and Mind Health)

Abstract

Chronological age is an imperfect estimate of molecular aging. Epigenetic age, derived from DNA methylation data, provides a more nuanced representation of aging-related biological processes. We examine the bidirectional relationship between epigenetic age and brain health events (stroke, dementia, late-life depression) using data from 4,018 participants. Participants with a prior brain health event are 4% epigenetically older (β = 0.04, SE = 0.01), indicating these conditions are associated with accelerated aging beyond that captured by chronological age. Additionally, a one standard deviation increase in epigenetic age is associated with 70% higher odds of experiencing a brain health event in the next four years (OR = 1.70, 95% CI = 1.16–2.50), suggesting epigenetic age acceleration is not just a consequence but also a predictor of poor brain health. Mendelian Randomization analyses replicate these findings, supporting their causal nature. Our results support using epigenetic age as a biomarker to evaluate interventions aimed at preventing and promoting recovery after brain health events.

Suggested Citation

  • Cyprien A. Rivier & Natalia Szejko & Daniela Renedo & Santiago Clocchiatti-Tuozzo & Shufan Huo & Adam Havenon & Hongyu Zhao & Thomas M. Gill & Kevin N. Sheth & Guido J. Falcone, 2025. "Bidirectional relationship between epigenetic age and stroke, dementia, and late-life depression," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-54721-0
    DOI: 10.1038/s41467-024-54721-0
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    References listed on IDEAS

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