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Original Investigation
June 24, 2019

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

Author Affiliations
  • 1Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden
  • 2Department of Neurology, Skåne University Hospital, Malmö, Sweden
  • 3Memory Clinic, Skåne University Hospital, Malmö, Sweden
  • 4Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
  • 5Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  • 6Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
  • 7UK Dementia Research Institute at UCL, London, United Kingdom
  • 8Roche Diagnostics GmbH, Penzberg, Germany
  • 9Genentech, a Member of the Roche Group, Basel, Switzerland
JAMA Neurol. 2019;76(9):1060-1069. doi:10.1001/jamaneurol.2019.1632
Key Points

Question  Do plasma levels of β-amyloid 42, β-amyloid 40, and tau detect cerebral β-amyloid status when measured using fully automated immunoassays?

Findings  In 2 cross-sectional studies, plasma β-amyloid 42 to β-amyloid 40 ratio, measured using immunoassay, accurately predicted cerebral β-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.

Meaning  Blood-based β-amyloid 42 and β-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.


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 β-amyloid (Aβ) and tau measured using fully automated assays together with other blood-based biomarkers to detect cerebral Aβ.

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) Aβ42/Aβ40 ratio was used as the reference standard for brain Aβ status. Plasma Aβ42, Aβ40 and tau were measured using Elecsys immunoassays (Roche Diagnostics) and examined as predictors of Aβ 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 Aβ42 and Aβ40 predicted Aβ 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 Aβ42, Aβ40 and APOE. The results were similar in CU and cognitively impaired participants, and in younger and older participants. Applying the plasma Aβ42 and Aβ40 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 Aβ42, Aβ40, 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 Aβ42 and Aβ40 measured using Elecsys immunoassays predict Aβ 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 Aβ positivity in clinical AD trials to lower the costs and number of positron emission tomography scans or lumbar punctures.