Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques
Abstract
Background and Objectives
To determine the diagnostic accuracy of a plasma Aβ42/Aβ40 assay in classifying amyloid PET status across global research studies using samples collected by multiple centers that utilize different blood collection and processing protocols.
Methods
Plasma samples (n = 465) were obtained from 3 large Alzheimer disease (AD) research cohorts in the United States (n = 182), Australia (n = 183), and Sweden (n = 100). Plasma Aβ42/Aβ40 was measured by a high precision immunoprecipitation mass spectrometry (IPMS) assay and compared to the reference standards of amyloid PET and CSF Aβ42/Aβ40.
Results
In the combined cohort of 465 participants, plasma Aβ42/Aβ40 had good concordance with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.84, 95% confidence interval [CI] 0.80–0.87); concordance improved with the inclusion of APOE ε4 carrier status (AUC 0.88, 95% CI 0.85–0.91). The AUC of plasma Aβ42/Aβ40 with CSF amyloid status was 0.85 (95% CI 0.78–0.91) and improved to 0.93 (95% CI 0.89–0.97) with APOE ε4 status. These findings were consistent across the 3 cohorts, despite differences in protocols. The assay performed similarly in both cognitively unimpaired and impaired individuals.
Discussion
Plasma Aβ42/Aβ40 is a robust measure for detecting amyloid plaques and can be utilized to aid in the diagnosis of AD, identify those at risk for future dementia due to AD, and improve the diversity of populations enrolled in AD research and clinical trials.
Classification of Evidence
This study provides Class II evidence that plasma Aβ42/Aβ40, as measured by a high precision IPMS assay, accurately diagnoses brain amyloidosis in both cognitively unimpaired and impaired research participants.
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© 2021 American Academy of Neurology.
Publication History
Received: June 22, 2021
Accepted: December 6, 2021
Published online: December 14, 2021
Published in print: February 15, 2022
Disclosure
Y. Li and S.E. Schindler report no disclosures. J.G. Bollinger, V. Ovod, and K.G. Mawuenyega have submitted the US provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition” as coinventors and may receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. L.M. Shaw reports no disclosures. M.W. Weiner has served on the Advisory Boards for Cerecin/Accera, Alzheon, Inc., Nestle/Nestec, PCORI/PPRN, Dolby Family Ventures, National Institute on Aging (NIA), Boston University Alzheimer's Disease and CTE Center, MIRIADE at VUmc for Amsterdam UMC, Cytox, Indiana University, Acumen, Brain Health Registry, and ADNI; serves on the editorial boards for Alzheimer's & Dementia, TMRI, and MRI; has provided consulting and/or acted as a speaker for Cerecin Inc., Alzheimer's Drug Discovery Foundation (ADDF), BioClinica, The Buck Institute for Research on Aging, FUJIFILM-Toyama Chemical (Japan), Garfield Weston, Baird Equity Capital, University of Southern California, Guidepoint Insights, T3D Therapeutics, Cytox, and Japanese Organization for Medical Device Development, Inc. (JOMDD); and holds stock options with Alzheon, Inc., Alzeca, and Anven. C.L. Masters serves as ad hoc consultant with Actinogen, Acumen, Alterity/Prana, Biogen, Eisai, Lilly, and Roche. C.J. Fowler, J.Q. Trojanowski, M. Korecka, R. Martin, and S. Janelidze reports no disclosures. O. Hansson has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, GE Healthcare, Pfizer, and Roche; and in the past 2 years, he has received consultancy/speaker fees from AC Immune, Alzpath, Biogen, Cerveau, and Roche. R.J. Bateman co-founded C2N Diagnostics. Washington University and R.J. 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 and 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 NIH RF1AG061900 (R.J. Bateman, PI), R56AG061900 (R.J. Bateman, PI), and an anonymous Foundation (R.J. Bateman, PI). S.E.S. is supported by K23AG053426 (S.E. Schindler, PI). ADNI is supported by NIH grant 5U19AG024904-14, the National Institute of Biomedical Imaging and Bioengineering, and through contributions from the following: AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Co.; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Co.; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corp.; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Co.; and Transition Therapeutics. The Canadian Institutes of Health Research provided funds to support ADNI clinical sites in Canada. Private sector contributions were facilitated by the Foundation for the National Institutes of Health (fnih.org). The grantee organization is the Northern California Institute for Research and Education and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuroimaging at the University of Southern California. A complete listing of ADNI investigators can be found at adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf. L.M.S. is supported by the ADNI3 grant AG024904 to provide QC oversight on biomarker analyses and the ADNI BioBank at UPenn. The AIBL study (aibl.csiro.au/) is a consortium among Austin Health, CSIRO, Edith Cowan University, and the Florey Institute, The University of Melbourne. Partial financial support was provided by the Alzheimer's Association, the Alzheimer's Drug Discovery Foundation, an anonymous foundation, the Cooperative Research Centre for Mental Health, CSIRO Science and Industry Endowment Fund, the Dementia Collaborative Research Centres, the Victorian Government Operational Infrastructure Support program, the McCusker Alzheimer's Research Foundation, the National Health and Medical Research Council, and the Yulgilbar Foundation. The BioFINDER study was supported by the Knut and Alice Wallenberg Foundation (2017-0383), the Marianne and Marcus Wallenberg Foundation (2015.0125), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson's Disease) at Lund University, the Swedish Alzheimer Foundation (AF-939932), the Swedish Brain Foundation (FO2021-0293), The Parkinson Foundation of Sweden (1,280/20), the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Skåne University Hospital Foundation (2020-O000028), Regionalt Forskningsstöd (2020-0314), and the Swedish federal government under the ALF agreement (2018-Projekt0279). Doses of 18F-flutemetamol injection in BioFINDER were sponsored by GE Healthcare.
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