Plasma p-tau231 in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: A cross-sectional and longitudinal cohort study

INTRODUCTION: Plasma phosphorylated tau (p-tau)-231 is a promising biomarker for Alzheimer's disease (AD), particularly in preclinical stages. We evaluated its diagnostic value in presenilin 1 (PSEN1) E280A mutation carriers versus non-carriers and compared it to p-tau217 and neurofilament light chain (NfL). METHODS: We analyzed plasma p-tau231 in 722 carriers and 640 non-carriers (ages 18–75). Longitudinal data from 164 carriers and 132 non-carriers were available, with 137 carriers and 109 non-carriers having p-tau231, p-tau217, and NfL levels. Analyses used linear mixed effects models and restricted cubic splines. RESULTS: E280A carriers had higher p-tau231 levels than non-carriers (9.0 ± 7.4 vs. 5.2 ± 3.4 pg/mL, P < 0.001). Baseline p-tau231 levels correlated with age, distinguishing carriers at age 23. Rates of change differed at age 19, ≈ 25 years before cognitive impairment. In a subset, p-tau231 changes differentiated carriers by age 20, earlier than p-tau217 and NfL. DISCUSSION: Plasma p-tau231 is a sensitive biomarker for early AD detection and progression monitoring. Highlights: Plasma phosphorylated tau (p-tau)231 levels are associated with age in presenilin 1 carriers and non-carriers. Baseline p-tau231 levels diverged between carriers and non-carriers at age 23. Plasma p-tau231 changes distinguished carriers by age 19, at very early stages. P-tau231 longitudinal changes differentiate carriers earlier than p-tau217 or neurofilament light chain.