Highly specific plasma β‐amyloid assays on the fully automated platform predict brain β‐amyloid pathology determined by a Centiloid threshold of amyloid PET

Abstract

AbstractBackgroundThe U.S. Food and Drug Administration approved aducanumab for the treatment of Alzheimer’s disease (AD) under the accelerated approval pathway and several new drug candidates are currently in development or have been submitted for marketing authorization in the U.S. and other countries. Consequently, the necessity of pathological diagnosis of AD by confirming brain β‐amyloid (Aβ) pathology in routine clinical practice is increasing to ensure that appropriate AD patients can access these drugs. We reported the development of the fully automated plasma Aβ40 and Aβ42 immunoassays that showed high performance for predicting brain Aβ pathology defined by amyloid PET. Here, we present the effect of several markers on the performance of our plasma Aβ assays.MethodsPlasma Aβ40 and Aβ42 levels were measured using a fully automated platform (HISCLTM series). To assess the performance of plasma Aβ42/Aβ40 ratio for predicting brain Aβ pathology, two studies (discovery and validation studies) were performed using plasma samples obtained from the elenbecestat phase 3 program. Brain Aβ pathology was determined by amyloid PET Centiloid scale. A cut‐off of Centiloid unit was determined as 32.21 by performing a receiver operating characteristic (ROC) analysis and determination of the Youden Index using visual reads as the standard. To evaluate the clinical performance of our assays, area under the curve (AUC) was obtained by performing a ROC analysis. The model, incorporating age and APOE ε4 status, was also evaluated.ResultsPlasma Aβ42/Aβ40 ratio predicted brain Aβ pathology defined by amyloid PET with AUCs of 0.93 and 0.92 in the discovery and validation studies, respectively. The sensitivity and specificity were calculated as 97.5% and 80.8% in the discovery study and 94.5% and 78.0% in the validation study. The model incorporating age and APOE ε4 status didn’t show significant improvement for predicting brain Aβ pathology.ConclusionsPlasma Aβ42/Aβ40 ratio measured by our immunoassays achieved high accuracy to predict brain Aβ pathology, and age and APOE ε4 status didn’t contribute to improve the accuracy unlike most past reports from other groups. Our assays may contribute to a high‐throughput, less invasive diagnostic method for detecting brain Aβ pathology in routine clinical practice.