Clinical utility of an antibody‐free LC‐MS method to detect brain amyloid deposition in cognitively unimpaired individuals from the screening visit of the A4 Study

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.