Epigenetic clocks and longitudinal plasma biomarkers of Alzheimer's disease.

INTRODUCTION

Chronological age is the strongest risk factor for Alzheimer's disease and related dementias (ADRD). However, the association of accelerated biological aging relative to chronological age with ADRD pathology is unclear.

METHODS

In a cohort of 2,366 cognitively unimpaired older women from the Women's Health Initiative Memory Study, we examined associations of five baseline measures of epigenetic age acceleration (EAA) with 15-year changes in plasma ADRD biomarkers.

RESULTS

At baseline, higher AgeAccelPheno was associated with lower amyloid-β42 to amyloid-β40 (Aβ42:Aβ40) ratio, and higher AgeAccelGrim2 was associated with elevated neurofilament light (NfL). Longitudinally, higher DunedinPACE - which measures the pace of biological aging - was associated with faster increases in phosphorylated tau at threonine 181 (p-tau181), p-tau217, NfL, and glial fibrillary acidic protein (GFAP) over 15 years.

DISCUSSION: Accelerated biological aging, particularly as indicated by DunedinPACE, was associated with increasing levels of plasma ADRD biomarkers over time.