The roles of biomarkers in Alzheimer's disease clinical trials.

Biomarkers are essential to guide decision making in Alzheimer's disease (AD) clinical trials where they have a variety of contexts of use (COUs) including diagnosis, risk, pharmacodynamic response, prognosis, prediction, monitoring, and safety. The COU of biomarkers may differ by phase of drug development with Phase 1, 2, and 3 emphasizing different types of information for decision making. A variety of biomarkers are currently serving as pharmacodynamic outcomes in clinical trials including amyloid and tau PET and fluid measures of amyloid, tau, neurodegeneration, inflammation, and synaptic plasticity. Biomarker strategies are integrated throughout drug development programs from collection and assay performance to statistical analysis and data interpretation. Data interrogation approaches using artificial intelligence and machine learning may enhance the value of biomarker observations through integration of multimodal data. Emerging biomarkers that may play a role in future AD trials include proteomics, exosome assays of co-pathology occurring in AD, EEG, ocular measures, and digital biomarkers. Biomarkers inform drug development decision-making including termination of candidate agents without sufficient biomarker effects, resourcing of promising therapies impacting the fundamental features of AD, and accelerating the development of new therapies for those with or at risk for AD.