Epigenetic clocks and longitudinal plasma biomarkers of Alzheimer's disease

Abstract 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 2366 (873 with longitudinal data) cognitively unimpaired older women, we examined associations of seven baseline measures of epigenetic age acceleration (EAA) and pace of aging with 15‐year changes in plasma ADRD biomarkers. RESULTS At baseline, higher AgeAccelHorvath and AgeAccelPheno were associated with lower amyloid beta (Aβ) 42 to Aβ40 (Aβ42:Aβ40) ratio, and higher AgeAccelGrim2, PCPhenoAge, and PCGrimAge were associated with elevated neurofilament light (NfL). Longitudinally, higher baseline DunedinPACE – capturing the pace of biological aging – was associated with faster increases in tau phosphorylated at threonine 181 (p‐tau181), p‐tau217, NfL, and glial fibrillary acidic protein (GFAP) over 15 years. DISCUSSION Accelerated biological aging, particularly DunedinPACE, was associated with increasing levels of plasma ADRD biomarkers over time. Highlights We studied 2366 older women from the Women's Health Initiative Memory Study. AgeAccelHorvath and AgeAccelPheno were linked to lower plasma Aβ42:Aβ40 at baseline. AgeAccelGrim2, PCPhenoAge, and PCGrimAge were linked to higher plasma NfL at baseline. DunedinPACE was associated with faster increases in p‐tau181, p‐tau217, NfL, and GFAP.