Biomarker-guided decision making in clinical drug development for neurodegenerative disorders

Neurodegenerative disorders are characterized by complex neurobiological changes that are reflected in biomarker alterations detectable in blood, cerebrospinal fluid (CSF) and with brain imaging. As accessible proxies for processes that are difficult to measure, biomarkers are tools that hold increasingly important roles in drug development and clinical trial decision making. In the past few years, biomarkers have been the basis for accelerated approval of new therapies for Alzheimer disease and amyotrophic lateral sclerosis as surrogate end points reasonably likely to predict clinical benefit.Blood-based biomarkers are emerging for Alzheimer disease and other neurodegenerative disorders (for example, Parkinson disease, frontotemporal dementia), and some biomarkers may be informative across multiple disease states. Collection of CSF provides access to biomarkers not available in plasma, including markers of synaptic dysfunction and neuroinflammation. Molecular imaging is identifying an increasing array of targets, including amyloid plaques, neurofibrillary tangles, inflammation, mitochondrial dysfunction and synaptic density. In this Review, we consider how biomarkers can be implemented in clinical trials depending on their context of use, including providing information on disease risk and/or susceptibility, diagnosis, prognosis, pharmacodynamic outcomes, monitoring, prediction of response to therapy and safety. Informed choice of increasingly available biomarkers and rational deployment in clinical trials support drug development decision making and de-risk the drug development process for neurodegenerative disorders.