Plasma p-tau217 predicts PET-based pathological staging for precision Alzheimer disease assessment

Abstract

INTRODUCTION: While positron emission tomography (PET) is the standard for pathological staging, its limited availability necessitates accessible alternatives. We evaluated plasma biomarkers for detecting PET-based stages using single-axis (Thal/Braak) and integrated A/T composite models. METHODS: We enrolled 237 AD spectrum participants undergoing multimodal assessments including amyloid/tau PET and plasma biomarker analysis (phosphorylated tau [p-tau] 217, %p-tau217, and amyloid beta [A beta] 42/40 ratio). Detecting and discriminative performance was assessed using receiver operating characteristics (ROC) analysis and probability-based stage prediction. RESULTS: Plasma p-tau217-based biomarkers showed excellent detecting performance for early amyloid (Thal I-II; area under the curve values > 0.96) and intermediate tau (Braak III-IV; area under the curve values > 0.92). Probability-based prediction identified therapeutic window thresholds of 1.895-5.077 pg/mL. Notably, integrated A/T composite staging yielded highly consistent thresholds (< 3% variance). DISCUSSION: Plasma p-tau217-based biomarkers accurately reflect PET-based staging across frameworks. The convergent therapeutic window thresholds demonstrate robust biological transitions, enabling accessible identification of optimal candidates for disease-modifying therapies. Highlights center dot Plasma phosphorylated tau (p-tau) 217 and %p-tau217 were directly aligned with positron emission tomography (PET)-defined Alzheimer&apos;s disease pathology using both single-axis staging (amyloid Thal phases, tau Braak stages) and integrated A/T composite staging. center dot Plasma p-tau217-based biomarkers consistently outperformed the amyloid beta (A beta) 42/40 ratio, showing excellent discrimination for early amyloid pathology and intermediate tau burden across PET-based staging frameworks. center dot Probability-based modeling defined stage-specific operating points, including optimal cutoffs and 50% probability thresholds, revealing a convergent biomarkerdefined therapeutic window across single-axis and composite staging approaches. center dot These findings support a plasma-first pathological staging strategy to identify treatment-eligible patients and prioritize confirmatory PET, particularly in clinical settings with limited imaging availability.