Performance of Fully Automated Plasma Assays as Screening Tests for Alzheimer Disease-Related ß-Amyloid Status.

IMPORTANCE: Accurate blood-based biomarkers for Alzheimer disease (AD) might improve the diagnostic accuracy in primary care, referrals to memory clinics, and screenings for AD trials. OBJECTIVE: To examine the accuracy of plasma ß-amyloid (Aß) and tau measured using fully automated assays together with other blood-based biomarkers to detect cerebral Aß. DESIGN, SETTING, AND PARTICIPANTS: Two prospective, cross-sectional, multicenter studies. Study participants were consecutively enrolled between July 6, 2009, and February 11, 2015 (cohort 1), and between January 29, 2000, and October 11, 2006 (cohort 2). Data were analyzed in 2018. The first cohort comprised 842 participants (513 cognitively unimpaired [CU], 265 with mild cognitive impairment [MCI], and 64 with AD dementia) from the Swedish BioFINDER study. The validation cohort comprised 237 participants (34 CU, 109 MCI, and 94 AD dementia) from a German biomarker study. MAIN OUTCOME AND MEASURES: The cerebrospinal fluid (CSF) Aß42/Aß40 ratio was used as the reference standard for brain Aß status. Plasma Aß42, Aß40 and tau were measured using Elecsys immunoassays (Roche Diagnostics) and examined as predictors of Aß status in logistic regression models in cohort 1 and replicated in cohort 2. Plasma neurofilament light chain (NFL) and heavy chain (NFH) and APOE genotype were also examined in cohort 1. RESULTS: The mean (SD) age of the 842 participants in cohort 1 was 72 (5.6) years, with a range of 59 to 88 years, and 446 (52.5%) were female. For the 237 in cohort 2, mean (SD) age was 66 (10) years with a range of 23 to 85 years, and 120 (50.6%) were female. In cohort 1, plasma Aß42 and Aß40 predicted Aß status with an area under the receiver operating characteristic curve (AUC) of 0.80 (95% CI, 0.77-0.83). When adding APOE, the AUC increased significantly to 0.85 (95% CI, 0.82-0.88). Slight improvements were seen when adding plasma tau (AUC, 0.86; 95% CI, 0.83-0.88) or tau and NFL (AUC, 0.87; 95% CI, 0.84-0.89) to Aß42, Aß40 and APOE. The results were similar in CU and cognitively impaired participants, and in younger and older participants. Applying the plasma Aß42 and Aß40 model from cohort 1 in cohort 2 resulted in slightly higher AUC (0.86; 95% CI, 0.81-0.91), but plasma tau did not contribute. Using plasma Aß42, Aß40, and APOE in an AD trial screening scenario reduced positron emission tomography costs up to 30% to 50% depending on cutoff. CONCLUSIONS AND RELEVANCE: Plasma Aß42 and Aß40 measured using Elecsys immunoassays predict Aß status in all stages of AD with similar accuracy in a validation cohort. Their accuracy can be further increased by analyzing APOE genotype. Potential future applications of these blood tests include prescreening of Aß positivity in clinical AD trials to lower the costs and number of positron emission tomography scans or lumbar punctures.