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October 22, 2019; 93 (17) Article

High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis

Suzanne E. Schindler, James G. Bollinger, Vitaliy Ovod, Kwasi G. Mawuenyega, Yan Li, Brian A. Gordon, David M. Holtzman, John C. Morris, Tammie L.S. Benzinger, Chengjie Xiong, Anne M. Fagan, View ORCID ProfileRandall J. Bateman
First published August 1, 2019, DOI: https://doi.org/10.1212/WNL.0000000000008081
Suzanne E. Schindler
From the Department of Neurology (S.E.S., J.G.B., V.O., K.G.M., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Knight Alzheimer's Disease Research Center (S.E.S., B.A.G., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Division of Biostatistics (Y.L., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (D.M.H., A.M.F., R.J.B.), Washington University School of Medicine, St. Louis, MO.
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James G. Bollinger
From the Department of Neurology (S.E.S., J.G.B., V.O., K.G.M., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Knight Alzheimer's Disease Research Center (S.E.S., B.A.G., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Division of Biostatistics (Y.L., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (D.M.H., A.M.F., R.J.B.), Washington University School of Medicine, St. Louis, MO.
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Vitaliy Ovod
From the Department of Neurology (S.E.S., J.G.B., V.O., K.G.M., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Knight Alzheimer's Disease Research Center (S.E.S., B.A.G., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Division of Biostatistics (Y.L., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (D.M.H., A.M.F., R.J.B.), Washington University School of Medicine, St. Louis, MO.
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Kwasi G. Mawuenyega
From the Department of Neurology (S.E.S., J.G.B., V.O., K.G.M., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Knight Alzheimer's Disease Research Center (S.E.S., B.A.G., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Division of Biostatistics (Y.L., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (D.M.H., A.M.F., R.J.B.), Washington University School of Medicine, St. Louis, MO.
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Yan Li
From the Department of Neurology (S.E.S., J.G.B., V.O., K.G.M., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Knight Alzheimer's Disease Research Center (S.E.S., B.A.G., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Division of Biostatistics (Y.L., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (D.M.H., A.M.F., R.J.B.), Washington University School of Medicine, St. Louis, MO.
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Brian A. Gordon
From the Department of Neurology (S.E.S., J.G.B., V.O., K.G.M., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Knight Alzheimer's Disease Research Center (S.E.S., B.A.G., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Division of Biostatistics (Y.L., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (D.M.H., A.M.F., R.J.B.), Washington University School of Medicine, St. Louis, MO.
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David M. Holtzman
From the Department of Neurology (S.E.S., J.G.B., V.O., K.G.M., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Knight Alzheimer's Disease Research Center (S.E.S., B.A.G., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Division of Biostatistics (Y.L., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (D.M.H., A.M.F., R.J.B.), Washington University School of Medicine, St. Louis, MO.
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John C. Morris
From the Department of Neurology (S.E.S., J.G.B., V.O., K.G.M., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Knight Alzheimer's Disease Research Center (S.E.S., B.A.G., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Division of Biostatistics (Y.L., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (D.M.H., A.M.F., R.J.B.), Washington University School of Medicine, St. Louis, MO.
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Tammie L.S. Benzinger
From the Department of Neurology (S.E.S., J.G.B., V.O., K.G.M., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Knight Alzheimer's Disease Research Center (S.E.S., B.A.G., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Division of Biostatistics (Y.L., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (D.M.H., A.M.F., R.J.B.), Washington University School of Medicine, St. Louis, MO.
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Chengjie Xiong
From the Department of Neurology (S.E.S., J.G.B., V.O., K.G.M., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Knight Alzheimer's Disease Research Center (S.E.S., B.A.G., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Division of Biostatistics (Y.L., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (D.M.H., A.M.F., R.J.B.), Washington University School of Medicine, St. Louis, MO.
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Anne M. Fagan
From the Department of Neurology (S.E.S., J.G.B., V.O., K.G.M., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Knight Alzheimer's Disease Research Center (S.E.S., B.A.G., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Division of Biostatistics (Y.L., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (D.M.H., A.M.F., R.J.B.), Washington University School of Medicine, St. Louis, MO.
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Randall J. Bateman
From the Department of Neurology (S.E.S., J.G.B., V.O., K.G.M., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Knight Alzheimer's Disease Research Center (S.E.S., B.A.G., D.M.H., J.C.M., T.L.S.B., C.X., A.M.F., R.J.B.), Division of Biostatistics (Y.L., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (D.M.H., A.M.F., R.J.B.), Washington University School of Medicine, St. Louis, MO.
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Citation
High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis
Suzanne E. Schindler, James G. Bollinger, Vitaliy Ovod, Kwasi G. Mawuenyega, Yan Li, Brian A. Gordon, David M. Holtzman, John C. Morris, Tammie L.S. Benzinger, Chengjie Xiong, Anne M. Fagan, Randall J. Bateman
Neurology Oct 2019, 93 (17) e1647-e1659; DOI: 10.1212/WNL.0000000000008081

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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.

Glossary

A4 Prevention Study=
Anti-Amyloid Treatment in Alzheimer's Prevention Study;
Aβ=
β-amyloid;
AD=
Alzheimer disease;
ANOVA=
analysis of variance;
AUC=
area under the curve;
CDR=
Clinical Dementia Rating;
CI=
confidence interval;
CV=
coefficient of variation;
DMSO=
dimethyl sulfoxide;
IPMS=
immunoprecipitation mass spectrometry;
NPA=
negative percent agreement;
p-tau=
phosphorylated tau181;
PiB=
Pittsburgh compound B;
PPA=
positive percent agreement;
QC=
quality control;
ROC=
receiver operating characteristic;
SUVR=
standardized uptake value ratio

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Editorial, page 737

  • Class of Evidence: NPub.org/coe

  • Podcast: NPub.org/6dc9ia

  • Received January 16, 2019.
  • Accepted in final form June 17, 2019.
  • © 2019 American Academy of Neurology
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