RANDOMIZED clinical trials in Alzheimer’s disease have grown substantially in scale and complexity over the past three decades, with modern studies increasingly designed to capture slower and more subtle therapeutic effects.
A systematic review of 203 Phase II and III Alzheimer’s disease trials conducted between 1992 and 2024, encompassing 79,589 participants, revealed striking shifts in design features. Phase II trials increased their average sample size by 464%, rising from 42 to 237 participants, while Phase III trials grew by 50%, from 632 to 951 participants. Trial duration also lengthened significantly, with Phase II studies expanding from 16 to 46 weeks and Phase III from 20 to 71 weeks. These longer timelines reflect a focus on disease-modifying therapies that require extended evaluation, in contrast to earlier emphasis on symptomatic treatments.
Eligibility criteria have evolved as well. Since 2019, more than half of Alzheimer’s disease trials mandated biomarker confirmation for enrollment, compared with fewer than 3% before 2006. This shift underscores the central role of biological markers in modern Alzheimer’s disease research and trial design.
Funding sources also varied by therapeutic focus. Nearly all trials investigating anti-amyloid or anti-tau therapies were industry-funded (95.8%), while neurotransmitter-focused interventions (77.6%) and other categories (63.5%) showed greater diversity in funding support. Alongside these changes, trial transparency improved, with researchers more consistently including data availability statements, preregistering protocols, and reporting race and ethnicity of participants.
According to the analysis, Alzheimer’s disease clinical trials are increasingly structured to detect smaller and slower effects of therapeutic agents. The growing sample sizes, longer durations, and reliance on biomarker-based enrollment criteria may help explain recent successes in the field and provide a framework for evaluating future interventions.
Reference:
Aumont E et al. The Evolution of Randomized Clinical Trial Designs to Assess Therapeutics in Alzheimer Disease. JAMA Netw Open. 2025;8:e2529665.
