Effect of age on clinical trial outcome in participants with probable alzheimer's disease

Abstract

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.