High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis
Abstract
Objective
We examined whether plasma β-amyloid (Aβ)42/Aβ40, as measured by a high-precision assay, accurately diagnosed brain amyloidosis using amyloid PET or CSF p-tau181/Aβ42 as reference standards.
Methods
Using an immunoprecipitation and liquid chromatography–mass spectrometry assay, we measured Aβ42/Aβ40 in plasma and CSF samples from 158 mostly cognitively normal individuals that were collected within 18 months of an amyloid PET scan.
Results
Plasma Aβ42/Aβ40 had a high correspondence with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.88, 95% confidence interval [CI] 0.82–0.93) and CSF p-tau181/Aβ42 (AUC 0.85, 95% CI 0.79–0.92). The combination of plasma Aβ42/Aβ40, age, and APOE ε4 status had a very high correspondence with amyloid PET (AUC 0.94, 95% CI 0.90–0.97). Individuals with a negative amyloid PET scan at baseline and a positive plasma Aβ42/Aβ40 (<0.1218) had a 15-fold greater risk of conversion to amyloid PET-positive compared to individuals with a negative plasma Aβ42/Aβ40 (p = 0.01).
Conclusions
Plasma Aβ42/Aβ40, especially when combined with age and APOE ε4 status, accurately diagnoses brain amyloidosis and can be used to screen cognitively normal individuals for brain amyloidosis. Individuals with a negative amyloid PET scan and positive plasma Aβ42/Aβ40 are at increased risk for converting to amyloid PET-positive. Plasma Aβ42/Aβ40 could be used in prevention trials to screen for individuals likely to be amyloid PET-positive and at risk for Alzheimer disease dementia.
Classification of evidence
This study provides Class II evidence that plasma Aβ42/Aβ40 levels accurately determine amyloid PET status in cognitively normal research participants.
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Information & Authors
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© 2019 American Academy of Neurology.
Publication History
Received: January 16, 2019
Accepted: June 17, 2019
Published online: August 1, 2019
Published in print: October 22, 2019
Disclosure
S. Schindler has an immediate family member who recently owned stock in Eli Lilly. J. Bollinger has submitted the US provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition” as a coinventor. V. Ovod has submitted the US provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition” as a coinventor. K. Mawuenyega receives royalty income based on technology (methods for simultaneously measuring the in vivo metabolism of 2 or more isoforms of a biomolecule, and blood plasma assay) licensed by Washington University to C2N Diagnostics. He has submitted the US provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition” as a coinventor. Y. Li and B. Gordon report no disclosures relevant to the manuscript. D. Holtzman cofounded and is on the scientific advisory board of C2N Diagnostics. Washington University and Dr. Holtzman have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. He receives income from C2N Diagnostics for serving on the scientific advisory board. He is on the scientific advisory board of Denali and Proclara. His laboratory receives research support from AbbVie, Denali, and C2N Diagnostics. Neither J. Morris nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. Dr. Morris is currently participating in clinical trials of antidementia drugs from Eli Lilly and Company and Biogen. He is funded by NIH grants #P50AG005681, P01AG003991, P01AG026276, and UF1AG032438. T. Benzinger receives research support from Avid Radiopharmaceuticals, Eli Lilly, and Cerveau. She has or is currently participating in clinical trials of sponsored by Janssen, Eli Lilly, Pfizer, Biogen, and Roche. She has received travel support from the American Society for Neuroradiology, the Alzheimer's Association, and the People's Republic of China. C. Xiong reports no disclosures relevant to the manuscript. A. Fagan has received research funding from Biogen, Fujirebio, and Roche Diagnostics. She is a member of the scientific advisory boards for Roche, Genentech, and AbbVie and consults for Araclon/Griffols and DiamiR. R. Bateman cofounded C2N Diagnostics. Washington University and Dr. Bateman have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. He receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with Dr. Bateman as coinventor, has submitted the US provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition.” He consults for Roche, Genentech, AbbVie, Pfizer, Boehringer-Ingelheim, and Merck. Go to Neurology.org/N for full disclosures.
Study Funding
This study was supported by Anonymous Foundation (R.J. Bateman, PI), Alzheimer's Association Zenith grant (R.J. Bateman, PI), and National Institute on Aging grants NIH R56AG061900 (R.J. Bateman, PI), P01AG026276, P01AG03991, and P50AG05681 (J.C. Morris, PI). Additional support for imaging was provided by the Barnes Jewish Hospital Foundation and NIH P30NS098577, R01EB009352, and UL1TR000448. For Florbetapir F18 (AV45) imaging, doses and partial financial support were provided by Eli Lilly/Avid Radiopharmaceuticals. S.E. Schindler is supported by K23AG053426. B.A. Gordon is supported by K01AG053474 and the Barnes Jewish Hospital Foundation Willman Scholar Fund.
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