Effect of Age on Clinical Trial Outcome in Participants with Probable Alzheimer's Disease

Background: Age may affect treatment outcome in trials of mild probable Alzheimer's disease (AD). Objective: We examined age as a moderator of outcome in an exploratory study of deep brain stimulation targeting the fornix (DBS-f) region in participants with AD. Methods: Forty-two participants were implanted with DBS electrodes and randomized to double-blind DBS-f stimulation (on) or sham DBS-f (off) for 12 months. Results: The intervention was safe and well tolerated. However, the selected clinical measures did not differentiate between the on and off groups in the intent to treat (ITT) population. There was a significant age by time interaction with the Alzheimer's Disease Assessment Scale; ADAS-cog-13 (p = 0.028). Six of the 12 enrolled participants < 65 years old (50%) markedly declined on the ADAS-cog-13 versus only 6.7% of the 30 participants >= 65 years old regardless of treatment assignment (p = 0.005). While not significant, post-hoc analyses favored DBS-f off versus on over 12 months in the < 65 age group but favored DBS-f on versus off in the >= 65 age group on all clinical metrics. On the integrated Alzheimer's Disease rating scale (iADRS), the effect size contrasting DBS-f on versus off changed from +0.2 (favoring off) in the < 65 group to -0.52 (favoring on) in the >= 65 age group. Conclusion: The findings highlight issues with subject selection in clinical trials for AD. Faster disease progression in younger AD participants with different AD sub-types may influence the results. Biomarker confirmation and genotyping to differentiate AD subtypes is important for future clinical trials.

Automated summary

The study suggests that age may play a role in moderating treatment outcomes in Alzheimer's disease trials. Younger AD participants showed faster disease progression, which might be influenced by different AD subtypes. The findings emphasize the importance of biomarker confirmation and genotyping to differentiate AD subtypes in future clinical trials.