Clinical validity of second-generation tau PET tracers as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework

Abstract

Purpose In 2017, the Geneva Alzheimer’s disease (AD) strategic biomarker roadmap initiative proposed a framework of the systematic validation AD biomarkers to harmonize and accelerate their development and implementation in clinical practice. Here, we use this framework to examine the translatability of the second-generation tau PET tracers into the clinical context. Methods All available literature was systematically searched based on a set of search terms that related independently to analytic validity (phases 1–2), clinical validity (phase 3–4), and clinical utility (phase 5). The progress on each of the phases was determined based on scientific criteria applied for each phase and coded as fully, partially, preliminary achieved or not achieved at all. Results The validation of the second-generation tau PET tracers has successfully passed the analytical phase 1 of the strategic biomarker roadmap. Assay definition studies showed evidence on the superiority over first-generation tau PET tracers in terms of off-target binding. Studies have partially achieved the primary aim of the analytical validity stage (phase 2), and preliminary evidence has been provided for the assessment of covariates on PET signal retention. Studies investigating of the clinical validity in phases 3, 4, and 5 are still underway. Conclusion The current literature provides overall preliminary evidence on the establishment of the second-generation tau PET tracers into the clinical context, thereby successfully addressing some methodological issues from the tau PET tracer of the first generation. Nevertheless, bigger cohort studies, longitudinal follow-up, and examination of diverse disease population are still needed to gauge their clinical validity.

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 .…”

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

“…In parallel, a number of new ligands (second-generation tracers), purportedly with greater sensitivity and specificity, are currently under evaluation. Their level of maturity within the Strategic Biomarker Roadmap structure is summarized in the contributions by Wolters, Chiotis, and Bischof [5][6][7].…”