Clinical performance and robustness evaluation of plasma amyloid-β42/40 prescreening

Abstract

Introduction: Further evidence is needed to support the use of plasma amyloid β (Aβ) biomarkers as Alzheimer's disease prescreening tools. This study evaluated the clinical performance and robustness of plasma Aβ42/Aβ40 for amyloid positivity prescreening. Methods: Data were collected from 333 BioFINDER and 121 Alzheimer's Disease Neuroimaging Initiative study participants. Risk and predictive values versus percentile of plasma Aβ42/Aβ40 evaluated the actionability of plasma Aβ42/Aβ40, and simulations modeled the impact of potential uncertainties and biases. Amyloid PET was the brain amyloidosis reference standard. Results: Elecsys plasma Aβ42/Aβ40 could potentially rule out amyloid pathology in populations with low-to-moderate amyloid positivity prevalence. However, simulations showed small measurement or pre-analytical errors in Aβ42 and/or Aβ40 cause misclassifications, impacting sensitivity or specificity. The minor fold change between amyloid PET positive and negative cases explains the biomarkers low robustness. Discussion: Implementing plasma Aβ42/Aβ40 for routine clinical use may pose significant challenges, with misclassification risks. Highlights: Plasma Aβ42/Aβ40 ruled out amyloid PET positivity in a setting of low amyloid-positive prevalence. Including (pre-) analytical errors or measurement biases caused misclassifications. Plasma Aβ42/Aβ40 had a low inherent dynamic range, independent of analytical method. Other blood biomarkers may be easier to implement as robust prescreening tools.