. 2025 Feb;21(2):e14508.

doi: 10.1002/alz.14508. Epub 2025 Feb 5.

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

Nicholas J Ashton^{1

2

3

4}, Ashvini Keshavan⁵, Wagner S Brum^{1

6}, Ulf Andreasson¹, Burak Arslan¹, Mathias Droescher⁷, Stefan Barghorn⁷, Jeroen Vanbrabant⁸, Charlotte Lambrechts⁸, Maxime Van Loo⁸, Erik Stoops⁸, Shweta Iyengar⁹, HaYeun Ji⁹, Xiaomei Xu⁹, Alex Forrest-Hay⁹, Bingqing Zhang⁹, Yuling Luo⁹, Andreas Jeromin¹⁰, Manu Vandijck¹¹, Nathalie Le Bastard¹¹, Hartmuth Kolb¹², Gallen Triana-Baltzer¹³, Divya Bali¹⁴, Shorena Janelidze¹⁴, Shieh-Yueh Yang¹⁵, Catherine Demos¹⁶, Daniel Romero¹⁶, George Sigal¹⁶, Jacob Wohlstadter¹⁶, Kishore Malyavantham¹⁷, Meenakshi Khare¹⁷, Alexander Jethwa¹⁸, Laura Stoeckl¹⁸, Johan Gobom^{1

19}, Przemysław R Kac¹, Fernando Gonzalez-Ortiz¹, Laia Montoliu-Gaya¹, Oskar Hansson^{14

20}, Robert A Rissman²¹, Maria C Carrillo²², Leslie M Shaw²³, Kaj Blennow^{1

20

24

25}, Jonathan M Schott^{5

26}, Henrik Zetterberg^{1

20

26

27

28

29}

Affiliations

¹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
² King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, UK.
³ NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation Trust, London, UK.
⁴ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
⁵ Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁶ Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.
⁷ Neuroscience Research, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany.
⁸ ADx NeuroSciences N.V., Ghent, Belgium.
⁹ Alamar Biosciences, Inc., Fremont, California, USA.
¹⁰ ALZpath Inc., Carlsbad, California, USA.
¹¹ Fujirebio Europe N.V., Ghent, Belgium.
¹² Enigma Biomedical Group, San Diego, California, USA.
¹³ Neuroscience Biomarkers, Janssen Research and Development, San Diego, California, USA.
¹⁴ Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.
¹⁵ MagQu Co., Ltd., New Taipei City, Taiwan.
¹⁶ Meso Scale Diagnostics, LLC., Rockville, Maryland, USA.
¹⁷ Quanterix Corp, Billerica, Massachusetts, USA.
¹⁸ Roche Diagnostics GmbH, Penzberg, Germany.
¹⁹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
²⁰ Memory Clinic, Skåne University Hospital, Malmö, Sweden.
²¹ Alzheimer's Therapeutic Research Institute, Keck School of Medicine of the University of Southern California, San Diego, California, USA.
²² Division of Medical & Scientific Relations, Alzheimer's Association, Chicago, Illinois, USA.
²³ Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²⁴ Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
²⁵ Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, P.R. China.
²⁶ UK Dementia Research Institute, University College London, London, UK.
²⁷ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London, UK.
²⁸ Hong Kong Center for Neurodegenerative Diseases, Science Park, Hong Kong, China.
²⁹ School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.

PMID: 39907496
PMCID: PMC11851162
DOI: 10.1002/alz.14508

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

Nicholas J Ashton et al. Alzheimers Dement. 2025 Feb.

. 2025 Feb;21(2):e14508.

doi: 10.1002/alz.14508. Epub 2025 Feb 5.

Authors

Affiliations

¹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
² King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, UK.
³ NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation Trust, London, UK.
⁴ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
⁵ Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁶ Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.
⁷ Neuroscience Research, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany.
⁸ ADx NeuroSciences N.V., Ghent, Belgium.
⁹ Alamar Biosciences, Inc., Fremont, California, USA.
¹⁰ ALZpath Inc., Carlsbad, California, USA.
¹¹ Fujirebio Europe N.V., Ghent, Belgium.
¹² Enigma Biomedical Group, San Diego, California, USA.
¹³ Neuroscience Biomarkers, Janssen Research and Development, San Diego, California, USA.
¹⁴ Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.
¹⁵ MagQu Co., Ltd., New Taipei City, Taiwan.
¹⁶ Meso Scale Diagnostics, LLC., Rockville, Maryland, USA.
¹⁷ Quanterix Corp, Billerica, Massachusetts, USA.
¹⁸ Roche Diagnostics GmbH, Penzberg, Germany.
¹⁹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
²⁰ Memory Clinic, Skåne University Hospital, Malmö, Sweden.
²¹ Alzheimer's Therapeutic Research Institute, Keck School of Medicine of the University of Southern California, San Diego, California, USA.
²² Division of Medical & Scientific Relations, Alzheimer's Association, Chicago, Illinois, USA.
²³ Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²⁴ Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
²⁵ Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, P.R. China.
²⁶ UK Dementia Research Institute, University College London, London, UK.
²⁷ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London, UK.
²⁸ Hong Kong Center for Neurodegenerative Diseases, Science Park, Hong Kong, China.
²⁹ School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.

PMID: 39907496
PMCID: PMC11851162
DOI: 10.1002/alz.14508

Abstract

Introduction: The Alzheimer's Association Global Biomarker Standardization Consortium conducted a blinded case-control study to learn which phosphorylated tau (p-tau) assays provide the largest fold-changes in Alzheimer's disease (AD) versus non-AD and show commutability in measuring patient samples and candidate certified reference materials (CRMs).

Methods: Thirty-three different p-tau assays measured paired plasma and cerebrospinal fluid (CSF) from 40 participants (25 with "AD pathology" and 15 with "non-AD pathology" by CSF amyloid beta [Aβ]42/Aβ40 and p-tau181 criteria). Four CRMs were assessed.

Results: Plasma p-tau217 demonstrated higher fold-changes between AD and non-AD than other p-tau epitopes. Fujirebio LUMIPULSE G, UGOT IPMS, and Lilly MSD p-tau217 provided the highest fold-changes. Plasma p-tau217 showed the strongest correlations between plasma assays (rho = 0.81-0.97). The CRMs were not commutable across assays.

Discussion: Plasma p-tau217 showed larger fold-changes and better accuracy for detecting AD pathology in symptomatic individuals, with greater cross-platform agreement than other p-tau variants. Further work is needed to develop suitable CRMs facilitating cross-assay standardization.

Highlights: Paired plasma and cerebrospinal fluid (CSF) samples from twenty-five Alzheimer's disease (AD) and 15 non-AD patients were measured blind. Thirty-three plasma assays were compared, for phosphorylated tau-181 (p-tau181), 205, 212, 217 and 231. Plasma p-tau217 consistently had the highest fold-change and was best correlated between assays. Plasma-CSF correlations were weak to moderate. There was lack of commutability for four candidate reference materials.

Keywords: Alzheimer's disease; candidate reference materials; cerebrospinal fluid; commutability; immunoassay; phosphorylated tau; plasma.

PubMed Disclaimer

Conflict of interest statement

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, Alamar Biosciences, Biogen, VJDementia and Quanterix; consulted for Quanterix, TauRx, Neurogen Biomarking; served on advisory boards for Biogen, TauRx, and TargetALS; and has a pending patent application (PCT/US2024/037834 (WSGR Docket No. 58484‐709.601): Methods for Remote Blood Collection, Extraction and Analysis of Neuro Biomarkers). A.K., W.S.B., U.A., and B.A. have 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 an 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.X. is an employee of Alamar Biosciences. A.F‐H. is an employee of Alamar Biosciences. B.Z. is an employee of, and has stock or stock options in, Alamar Biosciences. Y.L. is an employee of Alamar Biosciences. A.J. is former employee of ALZpath, Inc., and has stock in ALZpath, Inc., and Quanterix, Inc. 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 Johnson and Johnson, and a current employee of the Enigma Biomedical Group; has undertaken paid consultancy for AviadoBio and Alector; has received an honorarium from Fortrea; and has a pending patient application for the Janssen CSF ptau217+ assay. D.B. has no conflicts of interest. G.T‐B. is an employee of Janssen R&D and has stock options; there is a pending patent application for the Janssen Simoa plasma p‐tau217+ assay. D.B. and S.J. have no conflicts of interest. S‐Y.Y. is an employee of MagQu Co., Ltd. C.D. is an 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.J. is a full‐time employee of, and has stock or stock options in, Roche Diagnostics GmbH, Penzberg, Germany. L.S. is a full‐time employee of, and has stock or stock options in, Roche Diagnostics GmbH, Penzberg, Germany. J.G., P.R.K., F.G.‐O., and L.M.‐G. have no conflicts of interest. O.H. has acquired research support (for the institution) from C2N Diagnostics. In the past 2 years, he has received consultancy/speaker fees from AC Immune, BioArctic, Biogen, Bristol Meyer Squibb, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens. R.A.R. has received consulting fees from Amydis Inc., Bioivt, Lexeo, Keystone Bio, Allyx, DiamiR, and PrecisionMed; and support for travel from Biogen. M.C.C. has no conflicts of interest. L.M.S. has served as a consultant or on advisory boards for Biogen, Roche Diagnostics, and Fujirebio; and receives in‐kind support from Fujirebio and Roche Diagnostics automated immunoassay platforms and reagents. K.B. has served as a consultant, on advisory boards, or on 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 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, 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). COBAS and ELECSYS are trademarks of Roche. All other trademarks are the8 property of their respective owners. The Elecsys Phospho‐Tau (181P) CSF immunoassay is approved for clinical use. The Elecsys p‐Tau181 and p‐Tau217 prototype plasma immunoassays are not currently approved for clinical use or commercially available. Author disclosures are available in the Supporting Information.

Figures

**FIGURE 1**
Median fold‐change of plasma and CSF p‐tau biomarkers in the AD versus non‐AD group. Forest plots indicate the median fold‐change of plasma (A) and CSF (B) p‐tau variants in the AD pathology group compared with the non‐AD pathology group. Bars correspond to standard error. Table S4 and Table S5 numerically describe this plot. AD, Alzheimer's disease; CSF, cerebrospinal fluid; IMR, immunomagnetic reduction; IPMS, immunoprecipitation‐mass spectrometry; MSD, MesoScale Discovery; NULISA, NUcleic acid Linked Immunosorbent Assay; p‐tau, phosphorylated tau; Simoa, single‐molecule arrray; UGOT, University of Gothenburg.

**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 the solid black line indicates the mean regression line. In each panel, the text indicates the computed Passing–Bablok equation for each assay pair and Spearman's rho (ρ) alongside its level of statistical significance in brackets. ^†Units are pg/mL for all assays excepting NULISA, which provides relative quantification in NPQ (NULISA Protein Quantification) units; IPMS, which is measured in fmol/L; and IPMS ratio, which has no units. ns, not significant. *p < 0.05, **p < 0.01, ***p < 0.0001. IPMS, immunoprecipitation‐mass spectrometry; MSD, MesoScale Discovery; NULISA, NUcleic acid Linked Immunosorbent Assay; p‐tau217, tau phosphorylated at threonine 217; Simoa, single‐molecule array; UGOT, University of Gothenburg.

**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 the solid black line indicates the mean regression line. In each panel, the text indicates the computed Passing–Bablok equation for each assay pair and Spearman's rho (ρ) alongside its associated level of statistical significance in brackets. ^†Units are pg/mL for all assays except NULISA, which provides relative quantification in NPQ (NULISA Protein Quantification) units; IPMS, which is measured in fmol/L; and IPMS ratio, which has no units. ns, not significant. *p < 0.05, **p < 0.01, ***p < 0.0001. IMR, immunomagnetic reduction; IPMS, immunoprecipitation‐mass spectrometry; MSD, MesoScale Discovery; NULISA, NUcleic acid Linked Immunosorbent Assay; p‐tau181, tau phosphorylated at threonine 181; Simoa, single‐molecule array; UGOT, University of Gothenburg.

**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 the solid black line indicates the mean regression line. In each panel, the text indicates the computed Passing–Bablok equation for each assay pair and Spearman's rho (ρ) alongside its level of statistical significance in brackets. ^†Units are pg/mL for all assays except NULISA, which provides relative quantification in NPQ (NULISA Protein Quantification) units; IPMS, which is measured in fmol/L; and IPMS ratio, which has no units. ns, not significant. *p < 0.05, **, p < 0.01, ***p < 0.0001. IPMS, immunoprecipitation‐mass spectrometry; MSD, MesoScale Discovery; NULISA, Nucleic acid LInked Immunosorbent Assay; p‐tau231, tau phosphorylated at threonine 231; Simoa, single‐molecule array; UGOT, University of Gothenburg.

**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 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. ^†Units are pg/mL for all assays except NULISA, which provides relative quantification in NPQ (NULISA Protein Quantification) units. AD, Alzheimer's disease; CSF, cerebrospinal fluid; MSD, MesoScale Discovery; NULISA, NUcleic acid Linked Immunosorbent Assay, p‐tau217, tau phosphorylated at threonine 217; Simoa, single‐molecule array; UGOT, University of Gothenburg.

See this image and copyright information in PMC

Update of

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, Carillo MC, Shaw LM, Blennow K, Schott JM, Zetterberg H. Ashton NJ, et al. medRxiv [Preprint]. 2024 Aug 22:2024.08.22.24312244. doi: 10.1101/2024.08.22.24312244. medRxiv. 2024. Update in: Alzheimers Dement. 2025 Feb;21(2):e14508. doi: 10.1002/alz.14508. PMID: 39228740 Free PMC article. Updated. Preprint.

References

1. Jack CR Jr, Bennett DA, Blennow K, et al. NIA‐AA research framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535‐562. - PMC - PubMed
1. Hansson O. Biomarkers for neurodegenerative diseases. Nat Med. 2021;27(6):954‐963. - PubMed
1. Rissman RA, Langford O, Raman R, et al . Plasma Aβ42/Aβ40 and phospho‐tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer's disease. Alzheimers Dement. 2024;20(2):1214‐1224. - PMC - PubMed
1. Schindler SE, Bollinger JG, Ovod V, et al. High‐precision plasma beta‐amyloid 42/40 predicts current and future brain amyloidosis. Neurology. 2019;93(17):e1647‐e59. - PMC - PubMed
1. Nakamura A, Kaneko N, Villemagne VL, et al. High performance plasma amyloid‐beta biomarkers for Alzheimer's disease. Nature. 2018;554(7691):249‐254. - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical