
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.08.22.24312244
preprint
1
Article
The Alzheimers Association Global Biomarker Standardization Consortium (GBSC) plasma phospho-tau Round Robin study
Ashton Nicholas J http://orcid.org/0000-0002-3579-8804

Keshavan Ashvini http://orcid.org/0000-0003-1043-5721

Brum Wagner S http://orcid.org/0000-0002-9777-0559

Andreasson Ulf http://orcid.org/0000-0001-8622-052X

Arslan Burak http://orcid.org/0000-0001-7229-3226

Droescher Mathias http://orcid.org/0000-0003-0857-1425

Barghorn Stefan
Venbrabant Jeroen
Lambrechts Charlotte
Van Loo Maxime
Stoops Erik
Iyengar Shweta
Ji HaYeun
Xu Xiaomei
Forrest-Hay Alex
Zhang Bingqing
Luo Yuling
Jeromin Andreas
Vandijck Manu
Le Bastard Nathalie
Kolb Hartmuth http://orcid.org/0000-0003-2414-5792

Triana-Baltzer Gallen http://orcid.org/0000-0003-0612-1236

Bali Divya http://orcid.org/0000-0003-3178-1586

Janelidze Shorena http://orcid.org/0000-0003-2869-8378

Yang Shieh-Yueh http://orcid.org/0000-0002-7850-4597

Demos Catherine http://orcid.org/0000-0003-3914-1954

Romero Daniel
Sigal George http://orcid.org/0000-0001-7149-6400

Wohlstadter Jacob
Malyavantham Kishore http://orcid.org/0000-0002-0970-8684

Khare Meenakshi
Jethwa Alexander http://orcid.org/0000-0003-3869-8662

Stoeckl Laura
Gobom Johan http://orcid.org/0000-0001-6193-6193

Kac Przemyslaw R http://orcid.org/0000-0001-5083-0924

Gonzalez-Ortiz Fernando http://orcid.org/0000-0001-7897-9456

Montoliu-Gaya Laia http://orcid.org/0000-0001-7684-6318

Hansson Oskar http://orcid.org/0000-0001-8467-7286

Rissman Robert A http://orcid.org/0000-0001-9245-8278

Carillo Maria C
Shaw Leslie M
Blennow Kaj http://orcid.org/0000-0002-1890-4193

Schott Jonathan M http://orcid.org/0000-0003-2059-024X

Zetterberg Henrik http://orcid.org/0000-0003-3930-4354

22 8 2024
2024.08.22.24312244https://creativecommons.org/licenses/by-nd/4.0/ This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.
http://medrxiv.org/lookup/doi/10.1101/2024.08.22.24312244
nihpp-2024.08.22.24312244.pdf
BACKGROUND: Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimers disease (AD) pathology. Multiple p-tau biomarkers on several analytical platforms are poised for clinical use. The Alzheimers 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: Alzheimers Association (#ADSF-24-1284328-C)
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pmc
