TY - JOUR
T1 - A blood-based diagnostic test incorporating plasma Aβ42/40 ratio, ApoE proteotype, and age accurately identifies brain amyloid status
T2 - findings from a multi cohort validity analysis
AU - West, Tim
AU - Kirmess, Kristopher M.
AU - Meyer, Matthew R.
AU - Holubasch, Mary S.
AU - Knapik, Stephanie S.
AU - Hu, Yan
AU - Contois, John H.
AU - Jackson, Erin N.
AU - Harpstrite, Scott E.
AU - Bateman, Randall J.
AU - Holtzman, David M.
AU - Verghese, Philip B.
AU - Fogelman, Ilana
AU - Braunstein, Joel B.
AU - Yarasheski, Kevin E.
N1 - Funding Information:
This work was supported by NIH R44 AG059489, BrightFocus CA2016636, The Gerald and Henrietta Rauenhorst (GHR) Foundation, and the Alzheimer’s Drug Discovery Foundation (ADDF).
Funding Information:
The following Centers provided samples and data: Wisconsin ADRC Clinical, Neuropathology, and Biomarker Cores, and biostatistical support provided by the Data Management and Biostatistics Core (P50 AG033514); Banner Alzheimer?s Institute (R01 AG031581), Arizona Alzheimer?s Disease Core Center (P30 AG19610), and Arizona Department of Health Services (Contract 211002); University of Florida ? Mt. Sinai Medical Center Alzheimer?s Disease Research Center (P50 AG047266); Washington University Knight Alzheimer?s Disease Research Center (P50 AG005681, P01 AG003991, P01 AG026276).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Background: The development of blood-based biomarker tests that are accurate and robust for Alzheimer’s disease (AD) pathology have the potential to aid clinical diagnosis and facilitate enrollment in AD drug trials. We developed a high-resolution mass spectrometry (MS)-based test that quantifies plasma Aβ42 and Aβ40 concentrations and identifies the ApoE proteotype. We evaluated robustness, clinical performance, and commercial viability of this MS biomarker assay for distinguishing brain amyloid status. Methods: We used the novel MS assay to analyze 414 plasma samples that were collected, processed, and stored using site-specific protocols, from six independent US cohorts. We used receiver operating characteristic curve (ROC) analyses to assess assay performance and accuracy for predicting amyloid status (positive, negative, and standard uptake value ratio; SUVR). After plasma analysis, sites shared brain amyloid status, defined using diverse, site-specific methods and cutoff values; amyloid PET imaging using various tracers or CSF Aβ42/40 ratio. Results: Plasma Aβ42/40 ratio was significantly (p < 0.001) lower in the amyloid positive vs. negative participants in each cohort. The area under the ROC curve (AUC-ROC) was 0.81 (95% CI = 0.77–0.85) and the percent agreement between plasma Aβ42/40 and amyloid positivity was 75% at the optimal (Youden index) cutoff value. The AUC-ROC (0.86; 95% CI = 0.82–0.90) and accuracy (81%) for the plasma Aβ42/40 ratio improved after controlling for cohort heterogeneity. The AUC-ROC (0.90; 95% CI = 0.87–0.93) and accuracy (86%) improved further when Aβ42/40, ApoE4 copy number and participant age were included in the model. Conclusions: This mass spectrometry-based plasma biomarker test: has strong diagnostic performance; can accurately distinguish brain amyloid positive from amyloid negative individuals; may aid in the diagnostic evaluation process for Alzheimer’s disease; and may enhance the efficiency of enrolling participants into Alzheimer’s disease drug trials.
AB - Background: The development of blood-based biomarker tests that are accurate and robust for Alzheimer’s disease (AD) pathology have the potential to aid clinical diagnosis and facilitate enrollment in AD drug trials. We developed a high-resolution mass spectrometry (MS)-based test that quantifies plasma Aβ42 and Aβ40 concentrations and identifies the ApoE proteotype. We evaluated robustness, clinical performance, and commercial viability of this MS biomarker assay for distinguishing brain amyloid status. Methods: We used the novel MS assay to analyze 414 plasma samples that were collected, processed, and stored using site-specific protocols, from six independent US cohorts. We used receiver operating characteristic curve (ROC) analyses to assess assay performance and accuracy for predicting amyloid status (positive, negative, and standard uptake value ratio; SUVR). After plasma analysis, sites shared brain amyloid status, defined using diverse, site-specific methods and cutoff values; amyloid PET imaging using various tracers or CSF Aβ42/40 ratio. Results: Plasma Aβ42/40 ratio was significantly (p < 0.001) lower in the amyloid positive vs. negative participants in each cohort. The area under the ROC curve (AUC-ROC) was 0.81 (95% CI = 0.77–0.85) and the percent agreement between plasma Aβ42/40 and amyloid positivity was 75% at the optimal (Youden index) cutoff value. The AUC-ROC (0.86; 95% CI = 0.82–0.90) and accuracy (81%) for the plasma Aβ42/40 ratio improved after controlling for cohort heterogeneity. The AUC-ROC (0.90; 95% CI = 0.87–0.93) and accuracy (86%) improved further when Aβ42/40, ApoE4 copy number and participant age were included in the model. Conclusions: This mass spectrometry-based plasma biomarker test: has strong diagnostic performance; can accurately distinguish brain amyloid positive from amyloid negative individuals; may aid in the diagnostic evaluation process for Alzheimer’s disease; and may enhance the efficiency of enrolling participants into Alzheimer’s disease drug trials.
KW - Alzheimer’s disease
KW - Neurodegeneration, mass spectrometry
KW - Plasma biomarkers
UR - http://www.scopus.com/inward/record.url?scp=85105163079&partnerID=8YFLogxK
U2 - 10.1186/s13024-021-00451-6
DO - 10.1186/s13024-021-00451-6
M3 - Article
C2 - 33933117
AN - SCOPUS:85105163079
SN - 1750-1326
VL - 16
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
IS - 1
M1 - 30
ER -