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.

Keywords: Age; Alzheimer’s disease; clinical trials; deep brain stimulation; subject selection.

Fig. 1

Schematic of Advance AD study design (CONSORT).

Fig. 2

ADAS-cog-13 and CDR-SB mean score differences between DBS-f “on” and “off” groups from baseline to 12 months stratified by different age cutoffs^*. ^*Each bar represents the mean score difference between the DBS “on” versus DBS “off” participants in each age category. Positive mean score differences indicate that the DBS-f “on” group had less decline than the DBS-f “off” group whereas negative mean score differences indicate that the DBS-f “on” group had more decline.

Fig. 3

Change in iADRS from baseline to month 12 in ADvance 1 study. iADRS is the integrated Alzheimer’s Disease Rating Scale; negative mean change. scores indicate worsening from baseline.

Fig. 4

Distribution of ADAS-cog-13 score changes from baseline to 12 months. Negative ADAS-cog-13 change scores for each participant reflect improvement from baseline whereas positive change scores reflect progressive cognitive worsening from baseline.

Fig. 5

Trajectory of ADAS-cog-13 score changes in AD participants < 65 years old. Graphic reflects individual ADAS-cog-13 score changes from baseline in the DBS-f “on” and DBS-f “off” assigned participants < 65 years old; Negative change scores indicate improvement whereas positive scores indicate worsening from baseline.