Fully automated and highly specific plasma β-amyloid immunoassays predict β-amyloid status defined by amyloid positron emission tomography with high accuracy

Background: The availability of more accessible and affordable biomarkers for neural β-amyloid (Aβ) would be highly beneficial for clinicians, researchers, and patients. This study aimed to evaluate the effectiveness of fully automated plasma Aβ immunoassays, which have shown significant correlation with immunoprecipitation mass spectrometry assays, in predicting brain Aβ status as determined by amyloid positron emission tomography (PET) visual read assessments.

Methods: The plasma Aβ42/Aβ40 ratio was measured using a fully automated immunoassay platform (HISCL series) in two clinical studies—a discovery study and a validation study. The sample sets for these studies were retrospectively and randomly selected from participants with early Alzheimer’s disease (AD) identified during screening for the Phase 3 elenbecestat program.

Results: The discovery study included 197 participants (mean age 71.1 [8.5] years; 112 females), while the validation study included 200 participants (mean age 70.8 [7.9] years; 99 females). The plasma Aβ42/Aβ40 ratio accurately predicted amyloid PET visual read status, with areas under the receiver operating characteristic curves (AUCs) of 0.941 (95% CI 0.910-0.973) in the discovery study and 0.868 (95% CI 0.816-0.920) in the validation study. In the discovery study, a cutoff value of 0.102 was determined using the Youden Index, resulting in a sensitivity of 96.0% (95% CI 90.1-98.9%) and a specificity of 83.5% (95% CI 74.6-90.3%). Applying the same cutoff value in the validation study, sensitivity was 88.0% (95% CI 80.0-93.6%) and specificity was 72.0% (95% CI 62.1-80.5%).

Conclusions: The plasma Aβ42/Aβ40 ratio measured with the HISCL series demonstrated high accuracy in predicting amyloid PET status. Given that this blood-based immunoassay system is less invasive and more accessible than amyloid PET and cerebrospinal fluid testing, it holds promise for aiding in the diagnosis of AD in routine clinical practice.