Search

Abstract INTRODUCTION This study explored the ability of plasma amyloid beta (Aβ)42/Aβ40 to identify brain amyloid deposition in cognitively unimpaired (CU) individuals. METHODS Plasma Aβ was quantified with an antibody‐free high‐performance liquid chromatography tandem mass spectrometry method from Araclon Biotech (ABtest‐MS) in a subset of 731 CU individuals from the screening visit of the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study, to assess associations of Aβ42/Aβ40 with Aβ positron emission tomography (PET). RESULTS A model including Aβ42/Aβ40, age, apolipoprotein E ε4, and recruitment site identified Aβ PET status with an area under the curve of 0.88 and an overall accuracy of 81%. A plasma‐based pre‐screening step could save up to 42% of the total number of Aβ PET scans. DISCUSSION ABtest‐MS accurately identified brain amyloid deposition in a population of CU individuals, supporting its implementation in AD secondary prevention trials to reduce recruitment time and costs. Although a certain degree of heterogeneity is inherent to large and multicentric trials, ABtest‐MS could be more robust to pre‐analytical bias compared to other immunoprecipitation mass spectrometry methods. HIGHLIGHTS Plasma amyloid beta (Aβ)42/Aβ40 accurately identified brain Aβ deposition in cognitively unimpaired individuals from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study. The inclusion of the recruitment site in the predictive models has a non‐negligible effect. A plasma biomarker‐based model could reduce recruitment costs in Alzheimer's disease secondary prevention trials. Antibody‐free liquid chromatography mass spectrometry methods may be more robust to pre‐analytical variability than other platforms.

Abstract Introduction Blood‐based assays to measure brain amyloid beta (Aβ) deposition are an attractive alternative to the cerebrospinal fluid (CSF)–based assays currently used in clinical settings. In this study, we examined different blood‐based assays to measure Aβ and how they compare among centers and assays. Methods Aliquots from 81 plasma samples were distributed to 10 participating centers. Seven immunological assays and four mass‐spectrometric methods were used to measure plasma Aβ concentrations. Results Correlations were weak for Aβ42 while Aβ40 correlations were stronger. The ratio Aβ42/Aβ40 did not improve the correlations and showed weak correlations. Discussion The poor correlations for Aβ42 in plasma might have several potential explanations, such as the high levels of plasma proteins (compared to CSF), sensitivity to pre‐analytical sample handling and specificity, and cross‐reactivity of different antibodies. Different methods might also measure different pools of plasma Aβ42. We, however, hypothesize that greater correlations might be seen in future studies because many of the methods have been refined during completion of this study.