Clinical performance and robustness evaluation of plasma amyloid‐β_42/40 prescreening

Abstract

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 Aβ 42 /Aβ 40 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 Aβ 42 /Aβ 40 evaluated the actionability of plasma Aβ 42 /Aβ 40 , and simulations modeled the impact of potential uncertainties and biases. Amyloid PET was the brain amyloidosis reference standard. Results Elecsys plasma Aβ 42 /Aβ 40 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 Aβ 42 and/or Aβ 40 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 Aβ 42 /Aβ 40 for routine clinical use may pose significant challenges, with misclassification risks. Highlights Plasma Aβ 42 /Aβ 40 ruled out amyloid PET positivity in a setting of low amyloid‐positive prevalence. Including (pre‐) analytical errors or measurement biases caused misclassifications. Plasma Aβ 42 /Aβ 40 had a low inherent dynamic range, independent of analytical method. Other blood biomarkers may be easier to implement as robust prescreening tools.