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.