Plasma A42/A40 and phospho-tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer's disease

INTRODUCTION: Incorporating blood-based Alzheimer's disease biomarkers such as tau and amyloid beta (A beta) into screening algorithms may improve screening efficiency.METHODS: Plasma A beta, phosphorylated tau (p-tau)181, and p-tau217 concentration levels from AHEAD 3-45 study participants were measured using mass spectrometry. Tau concentration ratios for each proteoform were calculated to normalize for inter-individual differences. Receiver operating characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by > 20 Centiloids. Mixture of experts analysis assessed the value of including tau concentration ratios into the existing predictive algorithm for amyloid positron emission tomography status.RESULTS: The area under the receiver operating curve (AUC) was 0.87 for A beta 42/A beta 40, 0.74 for phosphorylated variant p-tau181 ratio (p-tau181/np-tau181), and 0.92 for phosphorylated variant p-tau217 ratio (p-tau217/np-tau217). The Plasma Predicted Centiloid (PPC), a predictive model including p-tau217/np-tau217, A beta 42/A beta 40, age, and apolipoprotein E improved AUC to 0.95.DISCUSSION: Including plasma p-tau217/np-tau217 along with A beta 42/A beta 40 in predictive algorithms may streamline screening preclinical individuals into anti-amyloid clinical trials. ClinicalTrials.gov Identifier: NCT04468659Highlights center dot The addition of plasma phosphorylated variant p-tau217 ratio (p-tau217/np-tau217) significantly improved plasma biomarker algorithms for identifying preclinical amyloid positron emission tomography positivity.center dot Prediction performance at higher NAV Centiloid levels was improved with p-tau217/np-tau217.center dot All models generated for this study are incorporated into the Plasma Predicted Centiloid (PPC) app for public use.