Abstract
BACKGROUND: This study examines whether phosphorylated plasma Tau217 ratio (pTau217R) can predict tau accumulation in different brain regions, as measured by positron emission tomography (PET) standardized uptake value ratio (SUVR), for staging Alzheimer's disease (AD). METHODS: Plasma pTau217R was measured using immunoprecipitation-mass spectrometry. Models for predicting tau PET SUVR, developed with 144 early AD individuals using [(18)F]MK6240, were validated in two validation sets, VS1 (98 early AD) and VS2 (47 preclinical/early AD with a different tracer, flortaucipir (Tauvid)), all amyloid-beta positive (Aβ+). RESULTS: The pTau217R-based model predicted tau levels up to an SUVR of 2 in multiple brain regions, effectively assessing tau status at different tau levels with receiver operating characteristic (ROC) curve areas of 0.84-0.95 in VS1 and 0.71-0.88 in VS2 (using a different tracer). It reduced PET scan needs by 65% while maintaining 95% sensitivity. DISCUSSION: PTau217R reliably predicts regional tau accumulation in early AD, reducing reliance on tau PET scans and broadening its clinical application. CLINICAL TRIAL REGISTRATION NUMBER: NCT03887455 (ClarityAD) HIGHLIGHTS: Developed a model using plasma pTau217R to predict tau levels across brain regions. pTau217R model outperformed models based on clinical, MRI, and other blood biomarkers. The model reliably predicted tau levels exceeding tau positivity and higher thresholds. Screening with pTau217R could reduce tau PET scans by 65% at 95% sensitivity. pTau217R model aids in disease staging and monitoring in early AD.