Plasma Aß42/Aß40 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 (Aß) into screening algorithms may improve screening efficiency. METHODS: Plasma Aß, 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 Aß42/Aß40, 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, Aß42/Aß40, age, and apolipoprotein E improved AUC to 0.95. DISCUSSION: Including plasma p-tau217/np-tau217 along with Aß42/Aß40 in predictive algorithms may streamline screening preclinical individuals into anti-amyloid clinical trials. CLINICALTRIALS: gov Identifier: NCT04468659 HIGHLIGHTS: 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. Prediction performance at higher NAV Centiloid levels was improved with p-tau217/np-tau217. All models generated for this study are incorporated into the Plasma Predicted Centiloid (PPC) app for public use.

Clinical validation of the PrecivityAD2 blood test: A mass spectrometry-based test with algorithm combining %p-tau217 and Aß42/40 ratio to identify presence of brain amyloid.

BACKGROUND: With the availability of disease-modifying therapies for Alzheimer's disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment. METHODS: High-throughput, mass spectrometry-based assays were used to measure %p-tau217 and amyloid beta (Aß)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET. RESULTS: The area under the receiver operating characteristic curve (AUC-ROC) for %p-tau217 (0.94) was statistically significantly higher than that for p-tau217 concentration (0.91). The AUC-ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status. DISCUSSION: The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET.