Repeated plasma p‐tau217 measurements to monitor clinical progression heterogeneity

Abstract INTRODUCTION Heterogeneity of clinical progression in Alzheimer's disease (AD) complicates the assessment of disease progression and treatment effects in trials. This study evaluates the potential of plasma phosphorylated tau‐217 (p‐tau217) to capture this heterogeneity. METHODS We used k‐means clustering to analyze cognitive trajectories in amyloid beta –positive (Aβ+) cognitively normal (CN) and mild cognitive impairment (MCI) participants from two independent cohorts. Cohort 1 included 186 participants (71 CN, 115 MCI; 507 observations) and Cohort 2 included 207 participants (64 CN, 144 MCI; 781 observations), both with up to 10 years of follow‐up. RESULTS Three progression clusters emerged in both cohorts: stable cognition, slow decline, and rapid decline—each including cases initially classified as CN or MCI. Baseline plasma p‐tau217 was linked to progression risk in both cohorts, whereas longitudinal increases in Cohort 1 were steepest in rapid decliners. DISCUSSION Plasma p‐tau217 may aid in capturing clinical heterogeneity and support stratification and monitoring of disease progression in clinical trials. Highlights k‐Means found stable, slow, and rapid cognitive decline clusters in amyloid beta–positive (Aβ+) cases. Higher baseline plasma phosphorylated tau‐217 (p‐tau217) levels predicted faster cognitive decline. Longitudinal increases in plasma p‐tau217 were steepest in rapid decliners. Plasma p‐tau217 tracks clinical progression heterogeneity in Aβ+ cases. Cognitive stage and amyloid alone may miss severity and risk in early‐stage Alzheimer's disease.