Associations of epigenetic age acceleration with cognitive function trajectories in the women’s health initiative memory study

Abstract Background Epigenetic age acceleration (AgeAccel) indicates faster biological aging relative to chronological age and has been independently associated with several age‐related outcomes. However, the cross‐sectional and longitudinal associations of AgeAccel with global cognitive function is understudied. Method We therefore studied 734 women (mean±SD baseline age = 70.3±4 years; 7.9% Black, 3.5% Hispanic/Latina, 88.6% White) who were free of cognitive impairment at the baseline examination of the Women’s Health Initiative (WHI) Memory Study (WHIMS,≥65 years enrolled in the WHI Hormone Therapy clinical trials between 1993‐1998). We measured global cognitive function annually with the Modified Mini Mental State Examination (3MS) through 2007 and the modified Telephone Interview for Cognitive Status (TICS‐m) from 2008‐2021. We measured extrinsic AgeAccel [EEAA] intrinsic AgeAccel [IEAA], AgeAccelPheno, and AgeAccelGrim in blood collected at baseline. AgeAccel measures were derived from chronological age and white blood cell counts (EEAA and IEAA), phenotypic age (AgeAccelPheno), or mortality (AgeAccelGrim). We estimated cross‐sectional AgeAccel‐3MS score associations in linear regression models and longitudinal AgeAccel‐3MS and TICS‐m score associations in linear mixed effects (LME) models adjusting for age, educational attainment, race, ethnicity, marital status, alcohol use, smoking, body mass index, comorbidities, hormone trial group assignment and physical activity. Result AgeAccel measures were not cross‐sectionally associated with 3MS scores or longitudinally associated with 3MS or TICS‐m scores over a mean (SD) follow‐up of 6.4 (2.0) and 17.2 (3.6) years, respectively. Cross‐sectional AgeAccel‐3MS associations (95% confidence intervals) per 1‐year increment in AgeAccel were ‐0.03 (‐0.08, 0.02) for EEAA, ‐0.01 (‐0.08, 0.05) for IEAA, ‐0.02 (‐0.07, 0.03) for AgeAccelPheno, and 0 (‐0.10, 0.10) for AgeAccelGrim. Corresponding annual 3MS changes per 1‐year increment in AgeAccel were 0 (‐0.01, 0.01) for EEAA, 0 (‐0.01, 0.01) for IEAA, 0 (‐0.01, 0.01) for AgeAccelPheno, and 0 (‐0.02, 0.02) for AgeAccelGrim. Annual TICS‐m changes per 1‐year increment in AgeAccel were 0.01 (‐0.01, 0.03) for EEAA, 0 (‐0.02, 0.02) for IEAA, ‐0.01 (‐0.02, 0.01) for AgeAccelPheno, and 0.01 (‐0.02, 0.04) for AgeAccelGrim. Conclusion Blood‐based AgeAccel measures were not significantly associated with global cognitive function among older women. Larger studies are needed to further examine AgeAccel‐global cognitive function associations.