Repeated plasma p-tau217 measurements to monitor clinical progression heterogeneity.

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.