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[Preprint]. 2024 Aug 22:2024.08.22.24312244.
doi: 10.1101/2024.08.22.24312244.

The Alzheimer's Association Global Biomarker Standardization Consortium (GBSC) plasma phospho-tau Round Robin study

Nicholas J Ashton  1   2   3   4 , Ashvini Keshavan  5 , Wagner S Brum  1   6 , Ulf Andreasson  1 , Burak Arslan  1 , Mathias Droescher  7 , Stefan Barghorn  7 , Jeroen Vanbrabant  8 , Charlotte Lambrechts  8 , Maxime Van Loo  8 , Erik Stoops  8 , Shweta Iyengar  9 , HaYeun Ji  9 , Xiaomei Xu  9 , Alex Forrest-Hay  9 , Bingqing Zhang  9 , Yuling Luo  9 , Andreas Jeromin  10 , Manu Vandijck  11 , Nathalie Le Bastard  11 , Hartmuth Kolb  12 , Gallen Triana-Baltzer  13 , Divya Bali  14 , Shorena Janelidze  14 , Shieh-Yueh Yang  15 , Catherine Demos  16 , Daniel Romero  16 , George Sigal  16 , Jacob Wohlstadter  16 , Kishore Malyavantham  17 , Meenakshi Khare  17 , Alexander Jethwa  18 , Laura Stoeckl  18 , Johan Gobom  1   19 , Przemysław R Kac  1 , Fernando Gonzalez-Ortiz  1 , Laia Montoliu-Gaya  1 , Oskar Hansson  14   20 , Robert A Rissman  21 , Maria C Carillo  22 , Leslie M Shaw  23 , Kaj Blennow  1   20   24   25 , Jonathan M Schott  5   26 , Henrik Zetterberg  1   20   26   27   28   29
Affiliations

The Alzheimer's Association Global Biomarker Standardization Consortium (GBSC) plasma phospho-tau Round Robin study

Nicholas J Ashton et al. medRxiv. .

Update in

  • The Alzheimer's Association Global Biomarker Standardization Consortium (GBSC) plasma phospho-tau Round Robin study.
    Ashton NJ, Keshavan A, Brum WS, Andreasson U, Arslan B, Droescher M, Barghorn S, Vanbrabant J, Lambrechts C, Van Loo M, Stoops E, Iyengar S, Ji H, Xu X, Forrest-Hay A, Zhang B, Luo Y, Jeromin A, Vandijck M, Bastard NL, Kolb H, Triana-Baltzer G, Bali D, Janelidze S, Yang SY, Demos C, Romero D, Sigal G, Wohlstadter J, Malyavantham K, Khare M, Jethwa A, Stoeckl L, Gobom J, Kac PR, Gonzalez-Ortiz F, Montoliu-Gaya L, Hansson O, Rissman RA, Carrillo MC, Shaw LM, Blennow K, Schott JM, Zetterberg H. Ashton NJ, et al. Alzheimers Dement. 2025 Feb;21(2):e14508. doi: 10.1002/alz.14508. Epub 2025 Feb 5. Alzheimers Dement. 2025. PMID: 39907496 Free PMC article.

Abstract

Background: Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer's disease (AD) pathology. Multiple p-tau biomarkers on several analytical platforms are poised for clinical use. The Alzheimer's Association Global Biomarker Standardisation Consortium plasma phospho-tau Round Robin study engaged assay developers in a blinded case-control study on plasma p-tau, aiming to learn which assays provide the largest fold-changes in AD compared to non-AD, have the strongest relationship between plasma and cerebrospinal fluid (CSF), and show the most consistent relationships between methods (commutability) in measuring both patient samples and candidate reference materials (CRM).

Methods: Thirty-three different p-tau biomarker assays, built on eight different analytical platforms, were used to quantify paired plasma and CSF samples from 40 participants. AD biomarker status was categorised as "AD pathology" (n=25) and "non-AD pathology" (n=15) by CSF Aβ42/Aβ40 (US-FDA; CE-IVDR) and p-tau181 (CE-IVDR) methods. The commutability of four CRM, at three concentrations, was assessed across assays.

Findings: Plasma p-tau217 consistently demonstrated higher fold-changes between AD and non-AD pathology groups, compared to other p-tau epitopes. Fujirebio LUMIPULSE G, UGOT IPMS, and Lilly MSD p-tau217 assays provided the highest median fold-changes. In CSF, p-tau217 assays also performed best, and exhibited substantially larger fold-changes than their plasma counterparts, despite similar diagnostic performance. P-tau217 showed the strongest correlations between plasma assays (rho=0.81 to 0.97). Plasma p-tau levels were weakly-to-moderately correlated with CSF p-tau, and correlations were non-significant within the AD group alone. The evaluated CRM were not commutable across assays.

Interpretation: Plasma p-tau217 measures had larger fold-changes and discriminative accuracies for detecting AD pathology, and better agreement across platforms than other plasma p-tau variants. Plasma and CSF markers of p-tau, measured by immunoassays, are not substantially correlated, questioning the interchangeability of their continuous relationship. Further work is warranted to understand the pathophysiology underlying this dissociation, and to develop suitable reference materials facilitating cross-assay standardisation.

Funding: Alzheimer's Association (#ADSF-24-1284328-C).

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Conflict of interest statement

CONFLICTS OF INTEREST All biomarker measurements were performed by the assay developers in-house without cost. ALZpath p-tau217 was performed at the University of Gothenburg (UGOT) and Lilly immunoassays were performed at the University of Lund. C2N Diagnostics declined to participate in the study. N.J.A. has given lectures in symposia sponsored by Eli-Lilly, Roche Diagnostics, and Quanterix. NJA has declined paid opportunities from ALZpath. A.K. has no conflicts of interest. W.S.B. has no conflicts of interest. L.G. has no conflicts of interest. U.A. has no conflicts of interest. B.A. has no conflicts of interest. M.D. is an employee of AbbVie and holds stock or stock options. S.B. is an employee of AbbVie and holds stock or stock options. J.V. is employee of ADx NeuroSciences. C.L. is an employee of ADx NeuroSciences. M.V.L. is an employee of ADx NeuroSciences. E.S. is an employee of ADx NeuroSciences. S.I. is an employee of Alamar Biosciences H.Y.J. is an employee of Alamar Biosciences X.Y. is an employee of Alamar Biosciences A.F-H. is an employee of Alamar Biosciences B.Z. is an employee of Alamar Biosciences Y.L. is an employee of Alamar Biosciences A.Jeromin is an employee of ALZpath, Inc., and has stock options. M.V. is an employee of Fujirebio Europe N.V. N.L.B. is an employee of Fujirebio Europe N.V H.K. is a former employee of Janssen R&D D.B. has no conflicts of interest. G.T-B. is an employee of Janssen R&D and has stock options. D.B. has no conflicts of interest. S.J. has no conflicts of interest. S-Y.Y is an employee of MagQu Co., Ltd.C.D. C.D. is employee of Meso Scale Diagnostics, LLC D.R. is an employee of Meso Scale Diagnostics, LLC G.S. is an employee of Meso Scale Diagnostics, LLC J.W. is an employee of Meso Scale Diagnostics, LLC K.M. is an employee of Quanterix M.K. is an employee of Quanterix A.Jethwa is a full-time employee of Roche Diagnostics GmbH, Penzberg, Germany. L.S. is a full-time employee of Roche Diagnostics GmbH, Penzberg, Germany. O.H. has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, C2N Diagnostics, Eli Lilly, Eisai, Fujirebio, GE Healthcare, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Alzpath, BioArctic, Biogen, Bristol Meyer Squibb, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens. R.R has no conflicts of interest. J.G. has no conflicts of interest. P.K. has no conflicts of interest. F.G-O. has no conflicts of interest. L.M-G. has no conflicts of interest. L.M.S. has served as a consultant or on advisory boards for Biogen, Roche Diagnostics, Fujirebio; receives grant support from NIA/ADNI with QC oversight responsibilities and in-kind support from Fujirebio and Roche Diagnostics automated immunoassay platforms and reagents. K.B. has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. J.M.S. has received research funding from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly); consulted for Roche Pharmaceuticals, Biogen, Merck, and Eli Lilly; given educational lectures sponsored by GE Healthcare, Eli Lilly, and Biogen; and is Chief Medical Officer for ARUK. H.Z. has served at 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, 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, 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).

Figures

Figure 1.
Figure 1.. Median fold-change of plasma and CSF p-tau biomarkers in AD vs non-AD group.
Forest plots indicate the median fold-change of plasma (A) and cerebrospinal fluid (CSF; B) p-tau variants in the AD pathology group compared with the non-AD pathology group. Bars correspond to standard error. Supplementary Table 4 and Supplementary Table 5 numerically describe this plot.
Figure 2.
Figure 2.. Correlations between all plasma p-tau217 assays.
Scatterplots represent the continuous associations between all plasma p-tau217 assays. The dots indicate biomarker concentration and solid black line indicate the mean regression line. In each panel, text indicates the computed Passing-Bablok equation for each assay pair and the Spearman’s rho (ρ) alongside its level of statistical significance in brackets. ns= not significant, *=p<0.05, **=p<0.01, ***=p<0.0001
Figure 3.
Figure 3.. Correlations between all plasma p-tau181 assays.
Scatterplots represent the continuous associations between all plasma p-tau181 assays. The dots indicate biomarker concentration and solid black line indicate the mean regression line. In each panel, text indicates the computed Passing-Bablok equation for each assay pair and the Spearman’s rho (ρ) alongside its associated level of statistical significance in brackets. ns= not significant, *=p<0.05, **=p<0.01, ***=p<0.0001
Figure 4.
Figure 4.. Correlations between all plasma p-tau231 assays.
Scatterplots represent the continuous associations between all plasma p-tau231 assays. The dots indicate biomarker concentration and solid black line indicate the mean regression line. In each panel, text indicates the computed Passing-Bablok equation for each assay pair and the Spearman’s rho (ρ) alongside its level of statistical significance in brackets. ns= not significant, *=p<0.05, **=p<0.01, ***=p<0.0001
Figure 5.
Figure 5.. Intra-assay correlations between plasma and CSF p-tau217 biomarkers.
Scatterplots represent the associations between biomarker measurements performed with the same assay in plasma (y-axis) and cerebrospinal fluid (CSF; x-axis), alongside the mean regression line with 95% confidence intervals, computed based on data from all the participants in the cohort. Red dots indicate participants from the AD group and blue dots indicate participants from the non-AD group, as defined per clinical evaluation and CSF Aβ42/Aβ40 status. In each panel, the text in black indicates the Spearman’s correlation coefficient for the entire cohort and associated p-value, with red text indicating the Spearman’s correlation coefficient and associated p-value for the AD group only.
See this image and copyright information in PMC

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