Markers on the road: not there yet, but making progress

The advent of reliable fully automated assays for amyloid-β in CSF¹ and efforts to standardize the handling of samples before measurement are among the most important recent developments in the search for fluid biomarkers, Antoine Leuzy (University of Lund, Sweden) told the AAIC2020 session. Steps towards a unified protocol for sample collection, storage and dealing with blood contamination have been proposed.²

Task Force roadmap tells us how far each marker has come and how far it still has to go

In relation to plasma markers, we now have early evidence that P-tau181 in blood is highly sensitive and highly specific in differentiating AD from other neurodegenerative disorders, he said.

Tracking the tracers

Compared with earlier agents, second-generation tau PET tracers offer significantly reduced off-target binding, reported Gérard Bischof (University of Köln, Germany). Pharmacokinetics are also good.³ Their clinical validation is under way, and a recent study of one second-generation tracer -- involving patients in the Swedish BioFINDER-2 trial -- showed encouragingly high specificity for AD-related tau and hence good potential as a diagnostic marker in differential diagnosis.⁴ 

Completing the clinical validation of these novel compounds requires standardization and aggregation of larger datasets. As for evaluating clinical utility, this will depend on the availability of the relevant compounds and the necessary on-site infrastructure, Dr Bischof said.

We need to know where we are going before we can say we’ve arrived

Tau markers included in standardized roadmap

When faced with so many potential markers, a comprehensive framework to standardize their evaluation is as important as the markers themselves. Hence the current focus of the Geneva-based international task force on a strategic roadmap adapted from an approach used in oncology.⁵ This AD framework now includes tau markers, which were not considered in the 2017 strategy.

For each marker, progress involves the sequential demonstration of:

• Analytical validity – standardization of assay readout within and between labs and of cut-offs that define abnormality. This requires studies to establish the potential influence of covariates such as age, sex, ethnicity and amyloid  and ApoE status
• Clinical validity – real-world ability to distinguish people with AD from healthy controls and from patients with non-AD neurodegeneration; and capacity to detect disease early. This phase includes assessing the implications of false negative results and the marker’s performance in predicting clinical outcomes, along with feasibility and an initial assessment of cost. It also encompasses comparison against other markers and efforts to improve accuracy by combining one marker with others.
• Clinical utility – this all-important implementation phase requires that deployment of a marker improves relevant outcomes for patients when used by qualified personnel and in compliance with guidelines.