Plasma Aβ42/Aβ40 and phospho‐tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer’s disease

Abstract Background Our data from several clinical trials of individuals with asymptomatic AD demonstrates that plasma Aβ42/40 quantification by mass spectrometry can serve as a reliable biomarker for predicting elevated brain amyloid as detected by PET. We investigated how adding plasma p‐tau measures to our plasma Aβ42/40 algorithm to streamline identification of eligible participants and reduce burden and trial cost. To determine if the addition of plasma p‐tau181 and/or p‐tau217 concentrations can improve plasma Aβ42/40 algorithms to correctly identify participants with amyloid burden of >20 centiloids with the NAV4694 tracer among individuals screening for participation in the AHEAD preclinical AD trial. Method Plasma amyloid and tau were measured using C 2 N Diagnostics mass spectrometry. Participant samples (N = 1085) collected prior to the incorporation of plasma Aβ42/40 testing during screening were used. Plasma samples consisted of those with adequate amyloid PET levels (n = 364; 33%) to be eligible for AHEAD and those who did not and screen failed (n = 747; 67%). We quantified Aβ (Aβ42/40) and tau species, including the phosphorylated (p‐tau) and non‐phosphorylated (np‐tau) forms of tau181 and tau217. A ratio of p‐tau to np‐tau was calculated (p‐tau181r and p‐tau217r) to normalize inter‐individual differences in np‐tau. We conducted Receiver Operating Characteristic (ROC) curve analyses fagainst amyloid PET status (>20 centiloids). We fit a Mixture of Experts model and included p‐tau181r and p‐tau217r in the predictive algorithm (Aβ42/40, Age and APOE) for amyloid PET status. Result Plasma samples from N = 1085 composed of 67% Female, 13.5% Hispanic, 3.7% Black or African American with a mean age of 67.6 (SD = 6.1) years. 45% of participants had at least one APOE4 allele. The Area Under the Curve (AUC) for Aβ42/40 was 0.87 (95% CI; 0.84, 0.89), consistent with prior reports. For plasma tau, we found AUCs of 0.74 (95% CI; 0.71, 0.77) with p‐tau181, to 0.91 (95% CI; 0.90, 0.93) with p‐tau217r. The model including covariates p‐tau217r, Aβ42/40, Age and APOE improved AUC to 0.95 (95% CI; 0.93, 0.96). Conclusion Our data suggests that plasma p‐tau217r in addition to Aβ42/40 ratio can significantly improve anti‐amyloid clinical trial screening burden and timelines for recruitment.