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Review
. 2021 Jul;48(7):2121-2139.
doi: 10.1007/s00259-021-05258-7. Epub 2021 Mar 5.

2020 update on the clinical validity of cerebrospinal fluid amyloid, tau, and phospho-tau as biomarkers for Alzheimer's disease in the context of a structured 5-phase development framework

A Leuzy  1 , N J Ashton  2   3   4 , N Mattsson-Carlgren  5   6   7 , A Dodich  8   9 , M Boccardi  10   11 , J Corre  12 , A Drzezga  13 , A Nordberg  14   15 , R Ossenkoppele  5   16 , H Zetterberg  2   17   18   19 , K Blennow  2   17 , G B Frisoni  10   20 , V Garibotto  8 , O Hansson  21   22
Affiliations
Review

2020 update on the clinical validity of cerebrospinal fluid amyloid, tau, and phospho-tau as biomarkers for Alzheimer's disease in the context of a structured 5-phase development framework

A Leuzy et al. Eur J Nucl Med Mol Imaging. 2021 Jul.

Abstract

Purpose: In the last decade, the research community has focused on defining reliable biomarkers for the early detection of Alzheimer's disease (AD) pathology. In 2017, the Geneva AD Biomarker Roadmap Initiative adapted a framework for the systematic validation of oncological biomarkers to cerebrospinal fluid (CSF) AD biomarkers-encompassing the 42 amino-acid isoform of amyloid-β (Aβ42), phosphorylated-tau (P-tau), and Total-tau (T-tau)-with the aim to accelerate their development and clinical implementation. The aim of this work is to update the current validation status of CSF AD biomarkers based on the Biomarker Roadmap methodology.

Methods: A panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of CSF AD biomarkers was assessed based on the Biomarker Roadmap methodology before the meeting and presented and discussed during the workshop.

Results: By comparison to the previous 2017 Geneva Roadmap meeting, the primary advances in CSF AD biomarkers have been in the area of a unified protocol for CSF sampling, handling and storage, the introduction of certified reference methods and materials for Aβ42, and the introduction of fully automated assays. Additional advances have occurred in the form of defining thresholds for biomarker positivity and assessing the impact of covariates on their discriminatory ability.

Conclusions: Though much has been achieved for phases one through three, much work remains in phases four (real world performance) and five (assessment of impact/cost). To a large degree, this will depend on the availability of disease-modifying treatments for AD, given these will make accurate and generally available diagnostic tools key to initiate therapy.

Keywords: Alzheimer’s disease; Aβ42; CSF; P-tau; T-tau; strategic roadmap.

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Conflict of interest statement

HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. OH has receiving grants from Roche, nonfinancial support from GE Healthcare, and grants from Biogen outside the submitted work.

AL, NJA, NMC, AD, MB, CJ, AD, AN, RO, GBF, and GB report no conflicts of interest.

Figures

Fig. 1
Fig. 1
A flowchart illustrating the development of CSF biomarkers for AD in the framework of Pepe et al. (2001) [1]. Abbreviations: AD, Alzheimer’s disease; CSF, cerebrospinal fluid; HC, healthy controls; MCI, mild cognitive impairment
See this image and copyright information in PMC

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