Longitudinal blood biomarker trajectories in preclinical Alzheimer's disease

Abstract INTRODUCTION Plasma biomarkers are altered years prior to Alzheimer's disease (AD) clinical onset. METHODS We measured longitudinal changes in plasma amyloid‐beta (Aβ) 42/40 ratio, pTau181, pTau231, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in a cohort of older adults at risk of AD ( n = 373 total, n = 229 with Aβ and tau positron emission tomography [PET] scans) considering genetic and demographic factors as possible modifiers of these markers’ progression. RESULTS Aβ 42/40 ratio concentrations decreased, while NfL and GFAP values increased over the 4‐year follow‐up. Apolipoprotein E ( APOE ) ε4 carriers showed faster increase in plasma pTau181 than non‐carriers. Older individuals showed a faster increase in plasma NfL, and females showed a faster increase in plasma GFAP values. In the PET subsample, individuals both Aβ‐PET and tau‐PET positive showed faster plasma pTau181 and GFAP increase compared to PET‐negative individuals. DISCUSSION Plasma markers can track biological change over time, with plasma pTau181 and GFAP markers showing longitudinal change in individuals with preclinical AD. Highlights Longitudinal increase of plasma pTau181 and glial fibrillary acidic protein (GFAP) can be measured in the preclinical phase of AD. Apolipoprotein E ε4 carriers experience faster increase in plasma pTau181 over time than non‐carriers. Female sex showed accelerated increase in plasma GFAP over time compared to males. Aβ 42/40 and pTau231 values are already abnormal at baseline in individuals with both amyloid and tau PET burden.