Epigenetic aging linked to MRI signatures of neurodegeneration but not general brain aging

“Epigenetic clocks of biological aging have been associated with cognitive impairment and dementia.”

BUFFALO, NY — April 23, 2026 — A new research paper was published in Volume 18 of Aging-US on April 7, 2026, titled “Association of epigenetic age acceleration with MRI biomarkers of aging and Alzheimer’s disease neurodegeneration.”

The study was led by first and corresponding author Linda K. McEvoy from the Kaiser Permanente Washington Health Research Institute, in collaboration with a multidisciplinary team of researchers across leading institutions in the United States and Europe.

In this study, the researchers examined whether epigenetic measures of biological aging are associated with structural brain changes linked to aging and Alzheimer’s disease. Using data from 1,196 older women enrolled in the Women’s Health Initiative Memory Study, they analyzed five widely used epigenetic clocks and compared them with MRI-derived measures obtained approximately eight years later.

The findings revealed a clear distinction between different aspects of aging. None of the epigenetic clocks were associated with accelerated brain aging as measured by the SPARE-BA index, a composite MRI marker of brain age. However, one specific clock—AgeAccelGrim2—was significantly associated with the Alzheimer’s Disease Pattern Similarity Score (AD-PS), a validated imaging biomarker linked to increased risk of dementia.

Further analyses suggested that this association was largely driven by epigenetic signatures related to smoking exposure. In particular, a DNA methylation marker reflecting cumulative smoking history was linked to reduced frontal and temporal lobe volumes—regions commonly affected in age-related neurodegeneration. Notably, no significant associations were observed with hippocampal or entorhinal cortex volumes, areas more directly implicated in early Alzheimer’s pathology.

“Taken together with prior findings, these results suggest that measures of epigenetic and brain age acceleration capture different aspects of biological aging, and that AgeAccelGrim2 is predictive of neurodegenerative changes associated with smoking that increase risk of dementia.”

The study highlights the complexity of biological aging and underscores that not all aging biomarkers reflect the same underlying processes. While epigenetic clocks are increasingly used to estimate biological age, their relationship with brain structure appears to depend on the specific pathways they capture—particularly those influenced by environmental exposures such as smoking.

Overall, these findings provide important insight into how molecular measures of aging relate to neuroimaging markers of brain health. By distinguishing between general brain aging and disease-related neurodegeneration, this work helps refine the use of epigenetic biomarkers in aging research and may support future efforts to identify individuals at risk for cognitive decline.

Paper DOI: https://doi.org/10.18632/aging.206369       

Corresponding author: Linda K. McEvoy – linda.k.mcevoy@kp.org

Abstract video: https://www.youtube.com/watch?v=kZiRjlKnnsI

Keywords: aging, epigenetic clocks, brain age, biological aging, smoking, frontal lobe

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