Target Trial Emulation for Drug Repurposing in Neurodegenerative Diseases

Drug repurposing can be a cost-effective approach to accelerate the development of disease-modifying therapies for neurodegenerative diseases. Definitive evaluation requires randomized controlled trials (RCTs), which remain the gold standard despite being slow, complex, and expensive. Observational studies of potential disease-modifying medications used in clinical practice can complement RCTs to prioritize candidates but are constrained by bias and design heterogeneity. The target trial emulation (TTE) framework provides a principled approach to strengthen causal inference by incorporating the key elements of a pragmatic RCT into observational analyses. In this article, we summarize the current conceptual foundations of TTE and its advantages for drug-repurposing research in neurodegenerative diseases: TTE offers an RCT-aligned, prespecified framework that curbs bias and generates transparent, decision-informing evidence. We examine the complexities inherent to these conditions, including slow disease progression, competing risks, outcome misclassification, and confounding, and review analytical strategies to address them. We also highlight common analytical practices that diverge from TTE principles which should be used with caution. We also discuss the limitations arising from the gap between idealized trials, target trials and their emulations, and explore future outlook for extending TTE with integration with real trial data. Overall, our study provides an accessible implementation guide to TTE, tailored to the complexities of neurodegenerative research, to support both wider application and more informed critical appraisal. Rigorous TTE can transform real-world data into a reliable source for identifying therapies and may become a standard component of evidence generation for neurodegenerative drug repurposing.