Plasma p-tau217 in Alzheimer’s disease is a dynamic gauge of progression heterogeneity, not a baseline stratifier

Abstract

Tau phosphorylated at threonine 217 (p-tau217) has moved from research novelty to clinical reality, but its greatest value lies in dynamic monitoring, not static stratification. The pace of adoption of the plasma measurement of p-tau217 now demands clear guidance on optimal use. Two complementary evidence strands inform this perspective. First, a multi-cohort evaluation of a commercial assay shows high concordance with amyloid and tau reference standards and supports a pragmatic three-zone interpretation, rule-out, indeterminate, and rule-in, that can streamline diagnostic pathways while preserving accuracy. Second, longitudinal analyses in amyloid-positive individuals reveal that the most informative property of p-tau217 is dynamic: steeper rises occur in those who decline faster, whereas baseline values substantially overlap across outcome groups. These findings show that plasma p-tau217 levels can be a complementary tool for triage, enrichment, and longitudinal monitoring, but not as a time-stable baseline stratifier for defining trial cohorts or assessing therapeutic efficacy. Stratification should instead anchor to independent, stable measures such as tau burden measured by positron emission tomography (PET), structural magnetic resonance imaging (MRI), and cognitive history, reducing misclassification and avoiding circular validation. Comparable scrutiny should be applied to other p-tau biomarkers and to composite measures, such as the p-tau217/Aβ_1–42 ratio, to rigorously define their risk-benefit profile, guide therapeutic evaluation, and maximize translational impact.

Keywords

plasma p-tau217 level / Alzheimer’s disease / blood-based biomarkers / longitudinal monitoring / clinical trial enrichment / baseline stratification / tau PET / pharmacodynamic biomarkers

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