Comparison of ELISA- and SIMOA-based quantification of plasma A[beta] ratios for early detection of cerebral amyloidosis

Background Blood-based amyloid biomarkers may provide a non-invasive, cost-effective and scalable manner for detecting cerebral amyloidosis in early disease stages. Methods In this prospective cross-sectional study, we quantified plasma A[beta].sub.1-42/A[beta].sub.1-40 ratios with both routinely available ELISAs and novel SIMOA Amyblood assays, and provided a head-to-head comparison of their performances to detect cerebral amyloidosis in a nondemented elderly cohort (n = 199). Participants were stratified according to amyloid-PET status, and the performance of plasma A[beta].sub.1-42/A[beta].sub.1-40 to detect cerebral amyloidosis was assessed using receiver operating characteristic analysis. We additionally investigated the correlations of plasma A[beta] ratios with amyloid-PET and CSF Alzheimer's disease biomarkers, as well as platform agreement using Passing-Bablok regression and Bland-Altman analysis for both A[beta] isoforms. Results ELISA and SIMOA plasma A[beta].sub.1-42/A[beta].sub.1-40 detected cerebral amyloidosis with identical accuracy (ELISA: area under curve (AUC) 0.78, 95% CI 0.72-0.84; SIMOA: AUC 0.79, 95% CI 0.73-0.85), and both increased the performance of a basic demographic model including only age and APOE-[epsilon]4 genotype (p [less than or equai to] 0.02). ELISA and SIMOA had positive predictive values of respectively 41% and 36% in cognitively normal elderly and negative predictive values all exceeding 88%. Plasma A[beta].sub.1-42/A[beta].sub.1-40 correlated similarly with amyloid-PET for both platforms (Spearman [rho] = - 0.32, p < 0.0001), yet correlations with CSF A[beta].sub.1-42/t-tau were stronger for ELISA ([rho] = 0.41, p = 0.002) than for SIMOA ([rho] = 0.29, p = 0.03). Plasma A[beta] levels demonstrated poor agreement between ELISA and SIMOA with concentrations of both A[beta].sub.1-42 and A[beta].sub.1-40 measured by SIMOA consistently underestimating those measured by ELISA. Conclusions ELISA and SIMOA demonstrated equivalent performances in detecting cerebral amyloidosis through plasma A[beta].sub.1-42/A[beta].sub.1-40, both with high negative predictive values, making them equally suitable non-invasive prescreening tools for clinical trials by reducing the number of necessary PET scans for clinical trial recruitment. Trial registration EudraCT 2009-014475-45 (registered on 23 Sept 2009) and EudraCT 2013-004671-12 (registered on 20 May 2014, Keywords: Preclinical Alzheimer's disease, Plasma, [beta]-Amyloid, Biomarkers