Pittsburgh plasma p-tau217: Classification accuracies for autosomal dominant and sporadic Alzheimer's disease in the community

INTRODUCTION: Most available phosphorylated tau (p-tau)217 immunoassays have similar performance. It is unclear if this is due to the use of the same antibody (the "ALZpath antibody"). We established and evaluated a novel p-tau217 assay that uses an alternative antibody and benchmarked the results against ALZpath-p-tau217. METHODS: After development and analytical validation of the University of Pittsburgh ("Pitt-p-tau217") method, clinical verification was performed in three independent cohorts (n = 363). RESULTS: Pitt-p-tau217 demonstrated high between-run stability, linearity, and specificity. Clinically, Pitt-p-tau217 differentiated neuropathologically confirmed PSEN1 mutation carriers from controls with area under the curve (AUC) = 0.94, and amyloid beta (Aβ) positron emission tomography (PET)-positive from Aβ PET-negative cognitively normal older adults with AUC up to 0.84, equivalent to ALZpath-p-tau217 results. Both Pitt-p-tau217 and ALZpath-p-tau217 were slightly elevated in tau PET-positive versus tau PET-negative participants. Between-assay correlations were up to 0.93. DISCUSSION: The new Pitt-p-tau217 assay exhibits high and reproducible classification accuracies for identifying individuals with biological evidence of Alzheimer's disease, equivalent to the widely used ALZpath-p-tau217. HIGHLIGHTS: We designed and developed an alternative assay to quantify plasma phosphorylated tau (p-tau)217, aiming to enhance accuracy and enable early detection of Alzheimer's disease (AD). Comprehensive analytical and clinical validation demonstrated that the new p-tau217 assay is a valuable and affordable resource for investigating AD pathophysiology. The new p-tau217 assay showed similar performance to the established ALZpath assay in staging and monitoring early AD.