Clinical performance and robustness evaluation of plasma amyloid‐β<sub>42/40</sub> prescreening
Christina Rabe, Tobias Bittner, Alexander Jethwa, Ivonne Suridjan, Ekaterina Manuilova, Michel Friesenhahn, Erik Stomrud, Henrik Zetterberg, Kaj Blennow, Oskar Hansson, for the Alzheimer's Disease Neuroimaging Initiative and the Swedish BioFINDER study
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.