Background/Objectives: Amyloid-PET is accurate but costly and capacity-limited. Blood-based biomarkers (BBMs), particularly plasma p-tau217, offer a scalable alternative for triaging patients. Objective of this study is to evaluate the diagnostic accuracy and clinical utility of plasma p-tau217 as a pre-screening tool for amyloid-PET positivity, identifying operating thresholds for rule-out and rule-in strategies. Methods: We analyzed 1681 participants from the ADNI cohort with concurrent plasma biomarkers (Fujirebio Lumipulse assays) and 18F-florbetapir PET. The primary outcome was discrimination of amyloid-PET positivity (Centiloid > 20). We compared p-tau217 alone against multivariable models (including Aβ42/40, GFAP, NfL, APOE) using Area Under the Curve (AUC) and Decision Curve Analysis (DCA). Two clinical thresholds were defined: a high-sensitivity “rule-out” cut-off (≥95% sensitivity) and a Youden-optimal “balanced” cut-off. These were validated using stratified bootstrap resampling. Results: Of 1681 participants, 679 (40.4%) were amyloid-positive. In the full sample, plasma p-tau217 alone achieved an AUC of 0.902 (95% CI 0.885–0.918). Operating thresholds were derived on a development split and applied to an independent validation split (N = 505). In the validation cohort, the high-sensitivity threshold (0.106 pg/mL) yielded 94.6% sensitivity and 93.7% NPV, effectively ruling out amyloid pathology. The Youden threshold (0.177 pg/mL) offered 78.9% sensitivity and 86.0% specificity. DCA demonstrated net benefit for p-tau217 screening over “PET all” strategies across clinically relevant probability ranges. Conclusions: Plasma p-tau217 provides high discrimination and clinically interpretable operating points for prioritizing confirmatory PET. Implementing a p-tau217-first strategy could significantly reduce unnecessary imaging without compromising diagnostic safety.
Ribisi et al. (Wed,) studied this question.