2026 American Academy of Neurology Abstract Website

Saman Arfaie¹, Etienne Aumont², Joseph Therriault², Angela Kwan², Giovanna Carello-Collar³, Brandon Hall², João-Pedro Ferrari-Souza³, Marcel Woo⁴, Arthur Macedo², Cécile Tissot⁵, Lydia Trudel², Nesrine Rahmouni², Stijn Servaes², Paolo Vitali¹, Jean-Paul Soucy², Tharick Pascoal⁶, Eduardo Zimmer⁷, Serge Gauthier⁸, Pedro Rosa Neto²
¹Neurology and Neurosugery, McGill University Research Centre for Studies in Aging, ²McGill University Research Centre for Studies in Aging, ³Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, ⁴6Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, ⁵Lawrence Berkeley National Laboratory, University of California, Berkeley, ⁶University of Pittsburgh, ⁷Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil, ⁸Douglas Hospital

Objective:

To describe temporal changes in the features of randomized clinical trials (RCTs) design for interventions in Alzheimer disease (AD).

Background:

The success of recent RCTs for AD, particularly those focusing on anti-amyloid therapies, has been discussed at length. However, the evolution of RCT design features for AD that preceded this success remain underexplored.

Design/Methods:

PubMed, Scopus, and Web of Science databases were searched in January 2025 for phase 2 and 3 AD RCTs published between January 1992 and December 2024. RCTs that investigated an intervention for AD, with a placebo or standard-of-care control group, were included.

Results:

203 RCTs with 79 589 participants testing interventions in AD. From 1992 to 2024, the mean sample size increased by 464% for phase 2 RCTs (from 42 to 237), and 50% for phase 3 RCTs (from 632 to 951), while the mean trial duration increased by 188% (from 16 to 46 weeks) for phase 2, and 256% (from 20 to 71 weeks) for phase 3 RCTs. This longer duration of RCTs may be partially attributed by a greater share of disease-modifying rather than symptomatic treatments. Similarly, more recent trials required AD biomarker evidence for enrollment (from 1 of 36 [2.7%] before 2006 to 40 of 76 [52.6%] since 2019). A substantial difference in the type of therapeutics researched was observed, with anti-amyloid and anti-tau RCTs being more likely to be funded by the pharmaceutical industry compared with neurotransmitter or other RCTs (anti-amyloid or anti-tau, 68 of 71 [95.8%]; neurotransmitter, 52 of 69 [77.6%]; other, 33 of 52 [63.5%]).

Conclusions:

AD RCTs have become larger and longer, such that they are powered to detect smaller clinical differences. The increased sample sizes and duration should enable the detection of smaller and more slowly occurring outcomes, which may lead to successful RCTs of therapies with slower and more subtle efficacy.