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

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.

The strategic biomarker roadmap for the validation of Alzheimer’s diagnostic biomarkers: methodological update

“…This work is part of a wider initiative, aimed to use the SBR and assess the validation status of biomarkers of tau pathology [25][26][27][28][29]. The initiative consisted of a workshop held in Geneva, November 11-12, 2019.…”

“…Four of the participant expert groups (viz., those led by Agneta Nordberg, Oskar Hansson, Rik Ossenkoppele, and Alexander Drzezga) have then assessed the validation status of CSF-, plasma-and imaging-tau AD biomarkers based on the evidence published until July 2020. Research strings and specific methods are reported in the five dedicated reviews [25][26][27][28][29].…”

“…In 2017, we used this framework to assess the validation status of the neuropsychological assessment (viz., episodic memory test) as a gateway to biomarker-based diagnosis [19], and of most consolidated AD biomarkers at that time, i.e., amyloid imaging [20], CSF [21], hippocampal atrophy [22], FDG-PET [23], and biomarkers for dementia with Lewy bodies [24], based on evidence published until 2015. In the present work, we revised the SBR to update it to the current A/T/N framework for research on AD and related disorders [1] and to enable proper assessment of biomarkers of tau pathology [25][26][27][28][29]. Such update was required, in that the diagnostic criteria adopted in 2017 entailed a relatively unclear role of Tau in the diagnostic procedure of AD.…”

“…[18,36]. These tables, adapted from previous evidence assessment for diagnostic biomarkers for neurocognitive disorders [37], are filled with the data extracted from the studies included in the reviews- [25][26][27][28][29]-and made available to the readers to complement our overall ass e s s m e n t ( h t t p s : / / d r i v e . s w i t c h .…”

“…Complying with the SBR validation steps, sequence, and methodology is therefore necessary to collect proper evidence having sufficiently high quality to support the downstream implementation of biomarkers into practice. The reviews assessing the validation status of biomarkers and mapping gaps and research priorities- [25][26][27][28][29]-are meant to detect gaps early on in the validation procedure and inform on how to adjust it, before extensive efforts are deployed in downstream studies that would provide faulty or biased data. Thus, keeping the methodology updated and performing periodical assessments of validation proceedings can improve the cost-effectiveness of biomarker validation.…”