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

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.

Diffusion MRI relates to plasma Aβ42/40 in PET negative participants without dementia

“…Plasma Aβ42/40 has emerged as a surrogate index for measuring brain amyloidosis and may have important implications for screening and detection of individuals at risk of AD and dementia. Several studies have now shown that plasma Aβ42/40 by high‐precision mass spectrometry predicts Aβ PET status with high area‐under‐the‐curve (AUC; range: 0.78–0.88) 3–8 …”

“…Several studies have now shown that plasma Aβ42/40 by high‐precision mass spectrometry predicts Aβ PET status with high area‐under‐the‐curve (AUC; range: 0.78–0.88). 3 , 4 , 5 , 6 , 7 , 8 …”