Cross-cohort validation and cutpoint estimation of the Janssen plasma p-tau217+ assay in predominantly cognitively normal community studies.

INTRODUCTION: Cross-cohort validation studies for plasma phosphorylated tau (p-tau) 217 are limited. We evaluated the Janssen plasma p-tau217+ assay and proposed a cutpoint value in three independent community-based cohorts. METHODS: We included n = 441 participants (age = 70.3 ± 7.3) from three independent community-based cohorts with amyloid-beta-positron emission tomography (Aβ-PET), tau-PET, clinical, and cognitive information. RESULTS: The cohorts had low pre-test probability (%Aβ positivity = 14.9-24.7) and were predominantly cognitively normal (> 73%). Plasma p-tau217+ had high accuracy for abnormal Aβ PET (areas under the curve [AUCs] = 81-86%), good correlation with Aβ-PET burden (0.336-0.397) that was highest in the cohort with the most Aβ-PET-positive participants, and the biomarker concentrations were highest in the joint Aβ-PET and tau-PET positive group. Negative predictive value (NPV) was high across cohorts (≤93%) but positive predictive value (PPV) was consistently poor (< 57%). Sensitivity and specificity averaged 75% and 84%, respectively. A combined cohort cutpoint of 0.05pg/ml gave AUC = 84.5%, NPV = 94%, PPV = 50%, sensitivity = 75%, and specificity = 84%. DISCUSSION: Plasma p-tau217+ can rule out Aβ pathophysiology due to Alzheimer's disease at the population level. Cohort-level %Aβ-PET positivity influences accuracies. HIGHLIGHTS: Plasma phosphorylated tau (p-tau) 217 assays have demonstrated potential to identify older adults with brain amyloid pathology due to Alzheimer's disease. Community-based studies are crucial for accessing the clinical validity of fluid biomarkers and their real-world applicability. We evaluated the Janssen plasma p-tau217+ assay in three community-based cohorts. Janssen plasma p-tau217+ identified amyloid-beta abnormalities across three diverse cohorts of community-dwelling older adults. High NPV indicates p-tau217+ as a good tool for initial screening to enrich for high-risk individuals particularly for cohort studies and clinical trial participation.