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.