TY - JOUR
T1 - Effect of Race on Prediction of Brain Amyloidosis by Plasma Aβ42/Aβ40, Phosphorylated Tau, and Neurofilament Light
AU - Schindler, Suzanne E.
AU - Karikari, Thomas K.
AU - Ashton, Nicholas J.
AU - Henson, Rachel L.
AU - Yarasheski, Kevin E.
AU - West, Tim
AU - Meyer, Mathew R.
AU - Kirmess, Kristopher M.
AU - Li, Yan
AU - Saef, Benjamin
AU - Moulder, Krista L.
AU - Bradford, David
AU - Fagan, Anne M.
AU - Gordon, Brian A.
AU - Benzinger, Tammie L.S.
AU - Balls-Berry, Joyce
AU - Bateman, Randall J.
AU - Xiong, Chengjie
AU - Zetterberg, Henrik
AU - Blennow, Kaj
AU - Morris, John C.
N1 - Funding Information:
S.E. Schindler has received data on behalf of Washington University from C2N Diagnostics at no cost. T.K. Karikari, N.J. Ashton, and R.L. Henson report no disclosures relevant to the manuscript. K.E. Yarasheski, T. West, M.R. Meyer, and K.M. Kirmess are employees of C2N Diagnostics, which offers the PrecivityAD test described in this article. Y. Li, B. Saef, K.L. Moulder, and D. Bradford report no disclosures relevant to the manuscript. A.M. Fagan has received research funding from Biogen, Centene, Fujirebio, and Roche Diagnostics; is a member of the scientific advisory boards for Roche Diagnostics, Genentech, and Diadem; and consults for DiamiR and Siemens Healthcare Diagnostics Inc. B.A. Gordon reports no disclosures relevant to the manuscript. T.L.S. Benzinger has investigator-initiated research funding from the NIH, the Alzheimer's Association, the Barnes-Jewish Hospital Foundation, and Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly); participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly, Biogen, Eisai, Janssen, and Roche; serves as an unpaid consultant to Eisai and Siemens; and is on the speaker's bureau for Biogen. J. Balls-Berry is a member of the patient advisory board and receives financial support for the Dartmouth University project Implementation of Uterine Fibroid Option Grid Patient Decision Aids Across Five Organizational Settings (UPFRONT; NCT03985449). R.J. Bateman co-founded C2N Diagnostics, receives income from C2N Diagnostics for serving on the scientific advisory board, and consults for Roche, Genentech, AbbVie, Pfizer, Boehringer-Ingelheim, and Merck. Dr. Bateman and Washington University 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. Washington University, with Dr. Bateman as coinventor, has submitted the US provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition.” C. Xiong consults for Diadem. H. Zetterberg has served on scientific advisory boards and/or as a consultant for Alector, Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, CogRx, and Red Abbey Labs; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. K. Blennow has served as a consultant, on advisory boards, or on data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. J.C. Morris is Chair of the Research Strategy Council of the Cure Alzheimer's Fund. Go to Neurology.org/N for full disclosures.
Funding Information:
This study was supported by National Institute on Aging grants R01AG070941 (S.E.S.), K23AG053426 (S.E.S.), P30AG066444 (J.C.M.), P01AG003991 (J.C.M.), P01AG026276 (J.C.M.), R01AG067505 (C.X.), and RF1R01AG053550 (C.X.) and the Cure Alzheimer's Fund (K.L.M.). C2N Diagnostics provided the plasma Aβ42/Aβ40 assays for this study. T.K.K. was funded by the Alzheimer's Association Research Fellowship (850325), the BrightFocus Foundation (A2020812F), the International Society for Neurochemistry's Career Development Grant, the Swedish Alzheimer Foundation (Alzheimerfonden; AF-930627), the Swedish Brain Foundation (Hjärnfonden; FO2020-0240), the Swedish Dementia Foundation (Demensförbundet), the Swedish Parkinson Foundation (Parkinsonfonden), the Gamla Tjänarinnor Foundation, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Agneta Prytz-Folkes & Gösta Folkes Foundation (2020-00124), the Gun and Bertil Stohnes Foundation, and the Anna Lisa and Brother Björnsson's Foundation. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018–02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF) USA (201809–2016862), the AD Strategic Fund and the Alzheimer's Association (ADSF-21-831376-C, ADSF-21-831381-C, and ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (FO2019-0228), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. K.B. is supported by the Swedish Research Council (2017-00915), the Swedish Alzheimer Foundation (AF-742881), Hjärnfonden, Sweden (FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (ALFGBG-715986), and the Alzheimer's Association 2021 Zenith Award (ZEN-21-848,495).
Publisher Copyright:
© American Academy of Neurology.
PY - 2022/7/19
Y1 - 2022/7/19
N2 - Background and ObjectivesTo evaluate whether plasma biomarkers of amyloid (Aβ42/Aβ40), tau (p-Tau181 and p-Tau231), and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups.MethodsIndividuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age, APOE ϵ4 carrier status, and cognitive status. Each participant underwent blood and CSF collection, and amyloid PET was performed in 103 participants (68%). Plasma Aβ42/Aβ40 was measured by a high-performance immunoprecipitation-mass spectrometry assay. Plasma p-Tau181, p-Tau231, and NfL were measured by Simoa immunoassays. CSF Aβ42/Aβ40 and amyloid PET status were used as primary and secondary reference standards of brain amyloidosis, respectively.ResultsThere were 76 matched pairs of AA and NHW participants (n = 152 total). For both AA and NHW groups, the median age was 68.4 years, 42% were APOE ϵ4 carriers, and 91% were cognitively normal. AA were less likely than NHW participants to have brain amyloidosis by CSF Aβ42/Aβ40 (22% vs 43% positive; p = 0.003). The receiver operating characteristic area under the curve of CSF Aβ42/Aβ40 status with the plasma biomarkers was as follows: Aβ42/Aβ40, 0.86 (95% CI 0.79-0.92); p-Tau181, 0.76 (0.68-0.84); p-Tau231, 0.69 (0.60-0.78); and NfL, 0.64 (0.55-0.73). In models predicting CSF Aβ42/Aβ40 status with plasma Aβ42/Aβ40 that included covariates (age, sex, APOE ϵ4 carrier status, race, and cognitive status), race did not affect the probability of CSF Aβ42/Aβ40 positivity. In similar models based on plasma p-Tau181, p-Tau231, or NfL, AA participants had a lower probability of CSF Aβ42/Aβ40 positivity (odds ratio 0.31 [95% CI 0.13-0.73], 0.30 [0.13-0.71], and 0.27 [0.12-0.64], respectively). Models of amyloid PET status yielded similar findings.DiscussionModels predicting brain amyloidosis using a high-performance plasma Aβ42/Aβ40 assay may provide an accurate and consistent measure of brain amyloidosis across AA and NHW groups, but models based on plasma p-Tau181, p-Tau231, and NfL may perform inconsistently and could result in disproportionate misdiagnosis of AA individuals.
AB - Background and ObjectivesTo evaluate whether plasma biomarkers of amyloid (Aβ42/Aβ40), tau (p-Tau181 and p-Tau231), and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups.MethodsIndividuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age, APOE ϵ4 carrier status, and cognitive status. Each participant underwent blood and CSF collection, and amyloid PET was performed in 103 participants (68%). Plasma Aβ42/Aβ40 was measured by a high-performance immunoprecipitation-mass spectrometry assay. Plasma p-Tau181, p-Tau231, and NfL were measured by Simoa immunoassays. CSF Aβ42/Aβ40 and amyloid PET status were used as primary and secondary reference standards of brain amyloidosis, respectively.ResultsThere were 76 matched pairs of AA and NHW participants (n = 152 total). For both AA and NHW groups, the median age was 68.4 years, 42% were APOE ϵ4 carriers, and 91% were cognitively normal. AA were less likely than NHW participants to have brain amyloidosis by CSF Aβ42/Aβ40 (22% vs 43% positive; p = 0.003). The receiver operating characteristic area under the curve of CSF Aβ42/Aβ40 status with the plasma biomarkers was as follows: Aβ42/Aβ40, 0.86 (95% CI 0.79-0.92); p-Tau181, 0.76 (0.68-0.84); p-Tau231, 0.69 (0.60-0.78); and NfL, 0.64 (0.55-0.73). In models predicting CSF Aβ42/Aβ40 status with plasma Aβ42/Aβ40 that included covariates (age, sex, APOE ϵ4 carrier status, race, and cognitive status), race did not affect the probability of CSF Aβ42/Aβ40 positivity. In similar models based on plasma p-Tau181, p-Tau231, or NfL, AA participants had a lower probability of CSF Aβ42/Aβ40 positivity (odds ratio 0.31 [95% CI 0.13-0.73], 0.30 [0.13-0.71], and 0.27 [0.12-0.64], respectively). Models of amyloid PET status yielded similar findings.DiscussionModels predicting brain amyloidosis using a high-performance plasma Aβ42/Aβ40 assay may provide an accurate and consistent measure of brain amyloidosis across AA and NHW groups, but models based on plasma p-Tau181, p-Tau231, and NfL may perform inconsistently and could result in disproportionate misdiagnosis of AA individuals.
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U2 - 10.1212/WNL.0000000000200358
DO - 10.1212/WNL.0000000000200358
M3 - Article
C2 - 35450967
AN - SCOPUS:85130307027
SN - 0028-3878
VL - 99
SP - E245-E257
JO - Neurology
JF - Neurology
IS - 3
ER -