Epigenetic Clocks of Biological Aging and Risk of Incident Mild Cognitive Impairment and Dementia: The Women's Health Initiative Memory Study

Aging is the strongest risk factor for dementia; however, few studies have examined the association of biological aging with incident dementia. We analyzed 6069 cognitively unimpaired women (mean age = 70.0 ± 3.8 years) in the Women's Health Initiative Memory Study to examine the association of accelerated biological aging, measured with second and third-generation epigenetic clocks (AgeAccelPheno and AgeAccelGrim2, and DunedinPACE, respectively) with incident mild cognitive impairment (MCI) and probable dementia. Multivariable Cox proportional hazards models adjusted for age, education, race, ethnicity, smoking, hormone therapy regimen, physical activity, body mass index, and estimated white blood cell counts. For comparison, we also examined first-generation epigenetic clocks (AgeAccelHorvath; AgeAccelHannum). We evaluated effect modification by age, race/ethnicity, hormone therapy regimen, menopause type (natural vs. surgical), and APOE ε4 carriage. There were 1307 incident MCI or probable dementia events over a median follow-up of 9.3 (25th percentile = 6.1, 75th percentile = 16.1) years. The adjusted HRs (95% CI; p-value) for incident MCI/probable dementia per one-standard deviation increment were 1.07 (1.01-1.15; p = 0.03) for DunedinPACE, 1.11 (1.02-1.20; p = 0.01) for AgeAccelGrim2, and 1.01 (0.95-1.07; p = 0.74) for AgeAccelPheno. Only AgeAccelGrim2 remained significant under the Bonferroni-corrected threshold for significance (p < 0.02). Other epigenetic clocks were not associated with incident MCI/probable dementia. There was no effect modification in most subgroup analyses (p-interaction ≥ 0.05). In this cohort study of older women, accelerated biological aging measured by AgeAccelGrim2 was associated with higher risk of incident MCI/probable dementia. These findings provide evidence linking epigenetic biomarkers of biological aging with MCI and dementia development, independent of chronological age.