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Comparative Study
. 2024 Nov;20(11):8074-8096.
doi: 10.1002/alz.14315. Epub 2024 Oct 12.

Head-to-head comparison of leading blood tests for Alzheimer's disease pathology

Suzanne E Schindler  1 , Kellen K Petersen  1 , Benjamin Saef  1 , Duygu Tosun  2 , Leslie M Shaw  3 , Henrik Zetterberg  4   5   6   7   8   9 , Jeffrey L Dage  10   11 , Kyle Ferber  12 , Gallen Triana-Baltzer  13 , Lei Du-Cuny  14 , Yan Li  1 , Janaky Coomaraswamy  15 , Michael Baratta  15 , Yulia Mordashova  14 , Ziad S Saad  13 , David L Raunig  15 , Nicholas J Ashton  4   16   17 , Emily A Meyers  18 , Carrie E Rubel  12 , Erin G Rosenbaugh  19 , Anthony W Bannon  20 , William Z Potter  21 ; Alzheimer's Disease Neuroimaging Initiative (ADNI) Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium Plasma Aβ and Phosphorylated Tau as Predictors of Amyloid and Tau Positivity in Alzheimer's Disease Project Team
Affiliations
Comparative Study

Head-to-head comparison of leading blood tests for Alzheimer's disease pathology

Suzanne E Schindler et al. Alzheimers Dement. 2024 Nov.

Erratum in

Abstract

Introduction: Blood tests have the potential to improve the accuracy of Alzheimer's disease (AD) clinical diagnosis, which will enable greater access to AD-specific treatments. This study compared leading commercial blood tests for amyloid pathology and other AD-related outcomes.

Methods: Plasma samples from the Alzheimer's Disease Neuroimaging Initiative were assayed with AD blood tests from C2N Diagnostics, Fujirebio Diagnostics, ALZPath, Janssen, Roche Diagnostics, and Quanterix. Outcomes measures were amyloid positron emission tomography (PET), tau PET, cortical thickness, and dementia severity. Logistic regression models assessed the classification accuracies of individual or combined plasma biomarkers for binarized outcomes, and Spearman correlations evaluated continuous relationships between individual plasma biomarkers and continuous outcomes.

Results: Measures of plasma p-tau217, either individually or in combination with other plasma biomarkers, had the strongest relationships with all AD outcomes.

Discussion: This study identified the plasma biomarker analytes and assays that most accurately classified amyloid pathology and other AD-related outcomes.

Highlights: Plasma p-tau217 measures most accurately classified amyloid and tau status. Plasma Aβ42/Aβ40 had relatively low accuracy in classification of amyloid status. Plasma p-tau217 measures had higher correlations with cortical thickness than NfL. Correlations of plasma biomarkers with dementia symptoms were relatively low.

Keywords: A/T/N; amyloid; biomarkers; blood; glial fibrillary acidic protein; neurofilament light; plasma; p‐tau; tau.

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Conflict of interest statement

S.E.S. has served on advisory boards and/or received speaking fees from Eisai, Eli Lilly, and Novo Nordisk. She has analyzed data from C2N Diagnostics that was provided to Washington University at no cost. S.E.S. has not directly received any research or personal compensation from C2N Diagnostics or any other diagnostics companies. K.K.P., B.S., D.T., and E.G.R. have nothing to disclose. L.M.S. receives funding from the NIA for ADNI4 and from NIA for the University of Pennsylvania ADRC P30 for the Biomarker Core. H.Z. has served on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). J.L.D. is an inventor on patents or patent applications of Eli Lilly and Company relating to the assays, methods, reagents, and/or compositions of matter for P‐tau assays and Aβ targeting therapeutics. J.L.D. has served as a consultant or on advisory boards for Eisai, Abbvie, Genotix Biotechnologies Inc, Gates Ventures, Karuna Therapeutics, AlzPath Inc., Cognito Therapeutics, Inc., and received research support from ADx Neurosciences, Fujirebio, AlzPath Inc., Roche Diagnostics and Eli Lilly and Company in the past 2 years. J.L.D. has received speaker fees from Eli Lilly and Company. J.L.D. is a founder and advisor for Monument Biosciences. J.L.D. has stock or stock options in Eli Lilly and Company, Genotix Biotechnologies, AlzPath Inc. and Monument Biosciences. K.F. and C.E.R. are employees of and may own stock in Biogen. G.T.B. and Z.S. are employed by Johnson & Johnson Innovative Medicine and may receive salary and stock for their employment. L.D.C. and Y.M. are employed by AbbVie Deutschland GmbH & Co. Y.L. is the co‐inventor of the technology “Novel Tau isoforms to predict onset of symptoms and dementia in Alzheimer's disease” which is in the process of licensing by C2N. J.C., M.B., and D.L.R. receive salary and company stock as compensation for their employment with Takeda Pharmaceutical Company Limited. N.J.A has received speaking fees from Eli Lilly, Biogen, Quanterix and Alamar Biosciences. E.A.M. is employed by the Alzheimer's Association. A.W.B. receives salary and company stock as compensation for his employment with AbbVie Inc. W.Z.P. was previously employed by the National Institute of Mental Health, and he is a stockholder in Merck & Co., Inc. He is a Co‐Chair Emeritus for the FNIH Biomarkers Consortium Neuroscience Steering Committee. Currently residing in Philadelphia, PA, he serves as a consultant for Karuna, Neurocrine, Neumarker, Vaaji, and receives grant support from the NIA along with stock options from Praxis Bioresearch. Author disclosures are available in the Supporting Information.

Figures

FIGURE 1
FIGURE 1
Correlation matrix of plasma biomarker measures in the full cohort. All individuals (n = 392) had plasma biomarker measures for the C2N PrecivityAD2, Fujirebio Lumipulse, ALZpath Quanterix, Janssen LucentAD Quanterix, and Roche NeuroToolKit assays. A sub‐cohort (n = 342) additionally had plasma biomarker measures for the Quanterix Neurology 4‐Plex assays. The unadjusted Spearman correlation of plasma biomarker measures with one another is shown. Redder colors are used for higher absolute correlations, and bluer colors are used for lower absolute correlations. Black boxes represent identity.
FIGURE 2
FIGURE 2
Receiver operating characteristics area under the curve plots for amyloid PET status in the full cohort. All individuals (n = 392) had plasma biomarker measures for the C2N PrecivityAD2, Fujirebio Lumipulse, ALZpath Quanterix, Janssen LucentAD Quanterix, and Roche NeuroToolKit assays. A sub‐cohort (n = 342) additionally had plasma biomarker measures for the Quanterix Neurology 4‐Plex assays. The best performing plasma biomarker measure or combination of measures from each company is shown for unadjusted models of amyloid PET > or ≤20 Centiloids. The solid black line represents a model of covariates alone. The dotted black line represents chance classification.
FIGURE 3
FIGURE 3
Classification accuracies of individual and combined plasma biomarker measures for key outcomes in the full cohort. All individuals (n = 392) had plasma biomarker measures for the C2N PrecivityAD2, Fujirebio Lumipulse, ALZpath Quanterix, Janssen LucentAD Quanterix, and Roche NeuroToolKit assays. A sub‐cohort (n = 342) additionally had plasma biomarker measures for the Quanterix Neurology 4‐Plex assays. The receiver operating characteristics area under the curve (AUC) point estimate (midpoint) and 95% confidence intervals are shown for classification of amyloid positron emission tomography (PET) status (> or ≤20 Centiloids), early tau PET status, cortical thickness status, and cognitive impairment status (CDR > 0 or = 0) by individual or combined plasma biomarker measures. The dashed vertical reference lines represent the AUCs for models including only covariates (age, sex, apolipoprotein E [APOE] genotype) as predictors. Please see the Methods section and Appendix A for definitions of early tau PET status and cortical thickness status.
FIGURE 4
FIGURE 4
Classification accuracies of individual and combined plasma biomarker measures for amyloid PET. Classification accuracies are shown for the full cohort (n = 392), cognitively impaired sub‐cohort (n = 192), and cognitively unimpaired sub‐cohort (n = 200). The receiver operating characteristics area under the curve (AUC) point estimate (midpoint) and 95% confidence intervals are shown for classification of amyloid positron emission tomography (PET) status (> or ≤20 Centiloids) by individual or combined plasma biomarker measures. The dashed vertical reference lines represent the AUCs for models including only covariates (age, sex, apolipoprotein [APOE] genotype) as predictors.
FIGURE 5
FIGURE 5
Scatterplots of plasma biomarker measures and amyloid positron emission tomography (PET) Centiloid. The best performing plasma biomarker measure from each company is shown. All individuals (n = 392) had plasma biomarker measures for the C2N PrecivityAD2, Fujirebio Lumipulse, ALZpath Quanterix, Janssen LucentAD Quanterix, and Roche NeuroToolKit assays. A sub‐cohort (n = 342) additionally had plasma biomarker measures for the Quanterix Neurology 4‐Plex assays. Point colors represent the following: blue, cognitively unimpaired and amyloid PET negative; green, cognitively impaired, and amyloid PET negative; orange, cognitively unimpaired and amyloid PET positive; red, cognitively impaired, and amyloid PET positive.
FIGURE 6
FIGURE 6
Correlations between individual plasma biomarker measures and key outcomes in the full cohort. All individuals (n = 392) had plasma biomarker measures for the C2N PrecivityAD2, Fujirebio Lumipulse, ALZpath Quanterix, Janssen LucentAD Quanterix, and Roche NeuroToolKit assays. A sub‐cohort (n = 342) additionally had plasma biomarker measures for the Quanterix Neurology 4‐Plex assays. The unadjusted Spearman correlation point estimate (midpoint) and 95% confidence intervals with plasma biomarker measures is shown for amyloid positron emission tomography (PET) Centiloid, the early tau PET measure, cortical thickness, and dementia severity by the Clinical Dementia Rating Sum of Boxes. The dashed vertical reference lines are arbitrary and presented to aide in visual interpretation.
FIGURE 7
FIGURE 7
Correlations between individual plasma biomarker measures and amyloid positron emission tomography (PET) Centiloid in sub‐cohorts. All individuals (n = 392) had plasma biomarker measures for the C2N PrecivityAD2, Fujirebio Lumipulse, ALZpath Quanterix, Janssen LucentAD Quanterix, and Roche NeuroToolKit assays. A sub‐cohort (n = 342) additionally had plasma biomarker measures for the Quanterix Neurology 4‐Plex assays. The unadjusted Spearman correlation point estimate (midpoint) and 95% confidence intervals are shown for amyloid PET Centiloid, the early tau PET measure, cortical thickness, and dementia severity by the Clinical Dementia Rating Sum of Boxes. The dashed vertical reference lines are arbitrary and presented to aide in visual interpretation.
FIGURE 8
FIGURE 8
Scatterplots of plasma biomarker measures and the early tau positron emission tomography (PET) measure. The best performing plasma biomarker measure from each company is shown. All individuals (n = 188) had plasma biomarker measures for the C2N PrecivityAD2, Fujirebio Lumipulse, ALZpath Quanterix, Janssen LucentAD Quanterix, and Roche NeuroToolKit assays. A sub‐cohort (n = 161) additionally had plasma biomarker measures for the Quanterix Neurology 4‐Plex assays. Point colors represent the following: blue, cognitively unimpaired and amyloid PET negative; green, cognitively impaired, and amyloid PET negative; orange, cognitively unimpaired and amyloid PET positive; red, cognitively impaired, and amyloid PET positive.
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Update of

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