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

Journal article
Authors S. Palmqvist
S. Janelidze
E. Stomrud
Henrik Zetterberg
J. Karl
K. Zink
T. Bittner
N. Mattsson
U. Eichenlaub
Kaj Blennow
O. Hansson
Published in Jama Neurology
Volume 76
Issue 9
Pages 1060-1069
ISSN 2168-6149
Publication year 2019
Published at Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Pages 1060-1069
Language en
Keywords mild cognitive impairment, association workgroups, diagnostic, guidelines, neurofilament light, national institute, blood biomarkers, cross-validation, tau, dementia, csf, Neurosciences & Neurology, long er, 1988, biometrics, v44, p837
Subject categories Neurosciences


Key PointsQuestionDo plasma levels of beta -amyloid 42, beta -amyloid 40, and tau detect cerebral beta -amyloid status when measured using fully automated immunoassays? FindingsIn 2 cross-sectional studies, plasma beta -amyloid 42 to beta -amyloid 40 ratio, measured using immunoassay, accurately predicted cerebral beta -amyloid status in all stages of Alzheimer disease in the BioFINDER cohort (n=842) and in an independent validation cohort (n=237). The diagnostic accuracy was further increased by analyzing APOE genotype. MeaningBlood-based beta -amyloid 42 and beta -amyloid 40 ratio together with APOE genotype may be used as prescreening tests in primary care and in clinical Alzheimer disease trials to lower the costs and number of positron emission tomography scans and lumbar punctures. This corss-sectional diagnostic study evaluates the accuracy of fully automated plasma assays in measuring plasma beta -amyloid and tau in patients with and without cognitive impairment in the Swedish BioFINDER study and an independent validation cohort. ImportanceAccurate blood-based biomarkers for Alzheimer disease (AD) might improve the diagnostic accuracy in primary care, referrals to memory clinics, and screenings for AD trials. ObjectiveTo examine the accuracy of plasma beta -amyloid (A beta) and tau measured using fully automated assays together with other blood-based biomarkers to detect cerebral A beta. Design, Setting, and ParticipantsTwo 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 MeasuresThe cerebrospinal fluid (CSF) A beta 42/A beta 40 ratio was used as the reference standard for brain A beta status. Plasma A beta 42, A beta 40 and tau were measured using Elecsys immunoassays (Roche Diagnostics) and examined as predictors of A beta 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. ResultsThe 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 A beta 42 and A beta 40 predicted A beta 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 A beta 42, A beta 40 and APOE. The results were similar in CU and cognitively impaired participants, and in younger and older participants. Applying the plasma A beta 42 and A beta 40 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 A beta 42, A beta 40, and APOE in an AD trial screening scenario reduced positron emission tomography costs up to 30% to 50% depending on cutoff. Conclusions and RelevancePlasma A beta 42 and A beta 40 measured using Elecsys immunoassays predict A beta 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 A beta positivity in clinical AD trials to lower the costs and number of positron emission tomography scans or lumbar punctures.

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