The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers

Abstract

Purpose The development of blood biomarkers that reflect Alzheimer’s disease (AD) pathophysiology (phosphorylated tau and amyloid-β) has offered potential as scalable tests for dementia differential diagnosis and early detection. In 2019, the Geneva AD Biomarker Roadmap Initiative included blood biomarkers in the systematic validation of AD biomarkers. Methods A panel of experts convened in November 2019 at a two-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of blood biomarkers was assessed based on the Biomarker Roadmap methodology and discussed fully during the workshop which also evaluated cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. Results Plasma p-tau has shown analytical validity (phase 2 primary aim 1) and first evidence of clinical validity (phase 3 primary aim 1), whereas the maturity level for Aβ remains to be partially achieved. Full and partial achievement has been assigned to p-tau and Aβ, respectively, in their associations to ante-mortem measures (phase 2 secondary aim 2). However, only preliminary evidence exists for the influence of covariates, assay comparison and cut-off criteria. Conclusions Despite the relative infancy of blood biomarkers, in comparison to CSF biomarkers, much has already been achieved for phases 1 through 3 – with p-tau having greater success in detecting AD and predicting disease progression. However, sufficient data about the effect of covariates on the biomarker measurement is lacking. No phase 4 (real-world performance) or phase 5 (assessment of impact/cost) aim has been tested, thus not achieved.

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.…”

Molecular imaging and fluid biomarkers of Alzheimer’s disease neuropathology: an opportunity for integrated diagnostics

“…CSF measures, currently routinely used in clinical practice, have improved their standardization across centers through unified protocols for sampling, handling, and storage and the introduction of fully automated assays [8]. The introduction of novel technologies with greatly increased sensitivity has also allowed the reliable detection of the molecular isoforms of amyloid and tau in the plasma, showing excellent accuracy to discriminate true positives from true negatives [9].…”

“…This entails finding strategies to quantify and compare complex dimensions that, beyond analytical and clinical validity, include costs, accessibility, and patient preferences and impact on health care and society. Multiple studies have shown that the results of molecular imaging and fluid assessment of the same molecular target, amyloid or tau, are correlated, but the agreement among measures is not perfect and variable across studies [8,9]. This is linked to the intrinsic nature of the test: molecular imaging tools can follow pathology accumulation across different brain topography stages, while changes in fluid might be more sensitive to the earliest change of state, from negative to positive, less sensitive to disease progression over more advanced stages and of course insensitive to topography.…”