Plasma p-tau217, p-tau181, and Aβ42 predict amyloid PET positivity in cognitively unimpaired adults.

BACKGROUND: Early detection of Alzheimer's disease (AD) pathology in cognitively unimpaired individuals is critical for preclinical intervention. Plasma biomarkers, especially phosphorylated tau217 (p-tau217), are promising predictors of amyloid-β (Aβ) accumulation. METHODS: In this cohort study, we analyzed data from cognitively unimpaired older adults in the A4 and LEARN studies (n = 1,407), comprising 452 participants with Aβ positron emission tomography (PET)-negative status and 955 participants with Aβ PET-positive status. We evaluated the accuracy of plasma biomarkers (p-tau217, p-tau181, Aβ42/40 ratio, and others) in predicting Aβ PET positivity using receiver operating characteristic analysis, comparing covariate-adjusted individual biomarker and biomarker-ratio models with a multivariable combined model integrating plasma biomarkers and covariates. (age, sex, apolipoprotein E [APOE] ε4 genotype). RESULTS: Plasma p-tau217 showed the strongest individual association with Aβ PET status (area under the curve [AUC], 0.85). A combined model integrating p-tau217, p-tau181, Aβ42, age, sex, and APOE ε4 achieved the highest overall discrimination (AUC, 0.87), although the improvement over the covariate-adjusted p-tau217 model was modest. CONCLUSIONS: Plasma p-tau217 showed the strongest individual performance for predicting Aβ PET positivity in cognitively unimpaired older adults. Adding other plasma biomarkers and clinical covariates provided a modest incremental improvement in classification performance. These findings support blood-based prescreening as a potential enrichment approach, while indicating that confirmatory amyloid assessment remains necessary when definitive Aβ status is required.