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

INTRODUCTIONCross-cohort validation studies for plasma p-tau217 are limited. We evaluated the Janssen plasma p-tau217+ assay and proposed a cutpoint value in three independent community-based cohorts. METHODSWe included n=441 participants (age=70.3{+/-}7.3), with A{beta}-PET, tau-PET, clinical and cognitive information. RESULTSThe cohorts had low pre-test probability (%A{beta} positivity=14.9-24.7) and were predominantly cognitively normal (>73%). Plasma p-tau217+ had high accuracy for abnormal A{beta} PET (AUCs=81-86%), good correlation with A{beta}-PET burden (0.336-0.397) that was highest in the cohort with the most A{beta}-PET-positive participants, and the biomarker concentrations were highest in the joint A{beta}-PET and tau-PET positive group. NPV was high across cohorts ([&le;]93%) but 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%. DISCUSSIONPlasma p-tau217+ can rule out A{beta} pathophysiology due to Alzheimers disease at the population level. Cohort-level %A{beta}-PET positivity influences accuracies.