Association of blood‐based epigenetic age acceleration with cognitive impairment and brain outcomes by cardiovascular disease among women

Abstract

AbstractBackgroundDNA methylation‐based epigenetic age acceleration (AgeAccel), an aging biomarker indicating faster biological aging relative to chronological age, is associated with many age‐related phenotypes. Blood‐based AgeAccel has been associated with lower cognitive function in several studies. However, there are limited data on associations of AgeAccel with mild cognitive impairment (MCI), dementia, and brain structure. Further, no prior study investigated whether associations of AgeAccel with cognitive and brain outcomes vary by cardiovascular disease (CVD), despite evidence linking vascular pathologies to both AgeAccel and dementia.MethodParticipants were 615 older women from a case‐cohort study of CVD in the Women’s Health Initiative (WHI) Clinical Trials and Observational Study who also enrolled in the WHI Memory Study (n=327 with incident CVD during follow‐up and n=288 without incident CVD). AgeAccel was measured in blood collected at baseline when women had no CVD or cognitive impairment. Women were followed for up to 25 years to determine centrally adjudicated diagnoses of MCI and dementia according to DSM‐IV criteria. A subset (n=90) had structural brain MRI scans performed ∼8 years after baseline. Associations between four measures of AgeAccel (intrinsic AgeAccel [IEAA], extrinsic AgeAccel [EEAA], AgeAccelPheno, and AgeAccelGrim) and risks for MCI/dementia incidence were estimated using Cox proportional hazards regression models. Associations of AgeAccel with brain volumes were examined using multiple linear regression models. Models were stratified by incident CVD status and adjusted for chronological age and other sociodemographic characteristics, lifestyle behaviors, and clinical factors.ResultAmong women who developed CVD, a 1‐year increase in IEAA was associated with higher risk of MCI (HR=1.10; 95% CI=1.03‐1.18), higher risk of combined MCI/dementia (HR=1.07; 95% CI=1.01‐1.13), and higher ventricular volume (in cm3; β=1.04; 95% CI=0.15‐1.94). A 1‐year increase in AgeAccelPheno was associated with higher risk of combined MCI/dementia (HR=1.05; 95% CI=1.00‐1.10) in women with incident CVD. The other two measures of AgeAccel were not associated with any outcome among women with incident CVD. No associations of AgeAccel with cognitive impairment or brain volumes were observed among women who did not develop CVD.ConclusionBlood‐based AgeAccel may be a marker of cognitive and brain health among women with underlying vascular pathologies.