Head-to-Head Comparison of 8 Plasma Amyloid-β 42/40 Assays in Alzheimer Disease

IMPORTANCE Blood-based tests for brain amyloid-beta (A beta) pathology are needed for widespread implementation of Alzheimer disease (AD) biomarkers in clinical care and to facilitate patient screening and monitoring of treatment responses in clinical trials. OBJECTIVE To compare the performance of plasma A beta 42/40 measured using 8 different A beta assays when detecting abnormal brain A beta status in patients with early AD. DESIGN, SETTING, AND PARTICIPANTS This study included 182 cognitively unimpaired participants and 104 patients with mild cognitive impairment from the BioFINDER cohort who were enrolled at 3 different hospitals in Sweden and underwent A beta positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) and plasma collection from 2010 to 2014. Plasma A beta 42/40 was measured using an immunoprecipitation-coupled mass spectrometry developed at Washington University (IP-MS-WashU), antibody-free liquid chromatography MS developed by Araclon (LC-MS-Arc), and immunoassays from Roche Diagnostics (IA-Elc); Euroimmun (IA-EI); and Amsterdam University Medical Center, ADx Neurosciences, and Quanterix (IA-N4PE). Plasma A beta 42/40 was also measured using an IP-MS-based method from Shimadzu in 200 participants (IP-MS-Shim) and an IP-MS-based method from the University of Gothenburg (IP-MS-UGOT) and another immunoassay from Quanterix (IA-Quan) among 227 participants. For validation, 122 participants (51 cognitively normal, 51 with mild cognitive impairment, and 20 with AD dementia) were included from the Alzheimer Disease Neuroimaging Initiative who underwent A beta-PET and plasma A beta assessments using IP-MS-WashU, IP-MS-Shim, IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays. MAIN OUTCOMES AND MEASURES Discriminative accuracy of plasma A beta 42/40 quantified using 8 different assays for abnormal CSF A beta 42/40 and A beta-PET status. RESULTS A total of 408 participants were included in this study. In the BioFINDER cohort, the mean (SD) age was 71.6 (5.6) years and 49.3% of the cohort were women. When identifying participants with abnormal CSF A beta 42/40 in the whole cohort, plasma IP-MS-WashU A beta 42/40 showed significantly higher accuracy (area under the receiver operating characteristic curve [AUC], 0.86; 95% CI, 0.81-0.90) than LC-MS-Arc A beta 42/40, IA-Elc A beta 42/40, IA-EI A beta 42/40, and IA-N4PE A beta 42/40 (AUC range, 0.69-0.78; P < .05). Plasma IP-MS-WashU A beta 42/40 performed significantly better than IP-MS-UGOT A beta 42/40 and IA-Quan A beta 42/40 (AUC, 0.84 vs 0.68 and 0.64, respectively; P < .001), while there was no difference in the AUCs between IP-MS-WashU A beta 42/40 and IP-MS-Shim A beta 42/40 (0.87 vs 0.83; P = .16) in the 2 subcohorts where these biomarkers were available. The results were similar when using A beta-PET as outcome. Plasma IPMS-WashU A beta 42/40 and IPMS-Shim A beta 42/40 showed highest coefficients for correlations with CSF A beta 42/40 (r range, 0.56-0.65). The BioFINDER results were replicated in the Alzheimer Disease Neuroimaging Initiative cohort (mean [SD] age, 72.4 [5.4] years; 43.4% women), where the IP-MS-WashU assay performed significantly better than the IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays but not the IP-MS-Shim assay. CONCLUSIONS AND RELEVANCE The results from 2 independent cohorts indicate that certain MS-based methods performed better than most of the immunoassays for plasma A beta 42/40 when detecting brain A beta pathology.