When is a biomarker an AD biomarker? Face versus construct validity and practical implications for differential application

Abstract

AbstractBackgroundTremendous recent developments have expanded the portfolio of biomarkers that have been described as directly specific for Alzheimer’s disease (AD) pathophysiology or assessing its consequences. This presentation will aim to provide a snapshot of the current validation and readiness status of imaging‐ and bodily fluid‐based AD biomarkers for different potential application scenarios.MethodAn overview of AD biomarker characteristics will be provided, focusing on established and emerging positron emission tomography (PET) and blood‐based biomarkers for amyloid‐β (Aβ) and tau pathology as well as glial activation and synaptic and neurodegeneration. Summarizing and discussing the foregoing talks in this session as well as reviewing relevant literature, emphasis will be placed on unique validation and application aspects of the respective biomarkers and on practical considerations.ResultAD‐related pathophysiology and its consequences can be assessed in vivo directly in the brain or in bodily fluids, most recently also in blood. The underlying modalities differ greatly in how their proposed face validity is confirmed, i.e. how specific the respective biomarker is to disease‐specific processes and how sensitive to longitudinal changes and different disease stages. Specifically, PET enables the direct mapping, quantification, and staging of regional pathology and related processes in the brain, while blood‐based measures generally provide information about peripheral, yet highly associated processes. Both yield continuous measures; however, this information is often discarded in favor of dichotomous, and global, biomarker classification. Novel blood‐based biomarkers have thus been claimed to have diagnostic and prognostic properties comparable with PET modalities. PET is limited to specialized centers, is resource‐hungry and involves radiation, while blood‐based biomarkers promise a scalable and accessible alternative or complement. However, the construct validity of blood biomarkers has hitherto mainly been established against relevant PET biomarkers. Finally, the various levels of harmonization and standardization of biomarker acquisition and analysis have major implications for their potential application.ConclusionThe field of AD biomarkers is more dynamic than ever. Snapshot evaluations of their current state of validity, their potential use and their practical limitations are needed to establish their potential differential, joint, and complementary roles in AD diagnostics, population screening, clinical trial enrichment, and use as trial outcome measure.