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.
Highlights
Age of onset can be a confounding moderating variable in clinical trials of probable Alzheimer’s disease (AD) because many younger, early onset AD participants have a more rapid cognitive decline than later onset participants that may be associated with distinct genetic subtypes [1,2,3,4,5]
We found that age affected the clinical outcome in study participants with probable mild AD treated with deep brain stimulation targeting the fornix (DBS-f) as the experimental condition [6]
The ADAS-cog-13 and Clinical Dementia Rating Scale (CDR) results failed to differentiate between AD participants assigned to DBS-f “on” or “off” after 12 months of blinded treatment the FDG-positron emission tomography (PET) imaging findings revealed that DBS-f “on” stimulation increased metabolic function relative to the sham treatment group [6, 14, 15]
Summary
Age of onset can be a confounding moderating variable in clinical trials of probable Alzheimer’s disease (AD) because many younger, early onset AD participants have a more rapid cognitive decline than later onset participants that may be associated with distinct genetic subtypes [1,2,3,4,5]. Using data obtained from 10 studies and 2,793 probable AD participants, Schneider and colleagues [4] reported that the younger participants had faster rates of cognitive decline than the older participants on the Alzheimer’s Disease Assessment Scale (ADAS-cog) over 12–24 months (p < 0.0001). Biomarker confirmation and genotyping to differentiate AD subtypes is important for future clinical trials
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