Abstract
Objective: To evaluate the safety, tolerability, adherence, and efficacy of 40Hz sensory stimulation therapy in subjects with Alzheimer’s disease (AD). Background: 40Hz gamma sensory stimulation diminishes AD pathology, neurodegeneration, and brain atrophy, synaptic and learning dysfunctions in transgenic mice carrying AD-related human pathological genes (Adaikkan & Tsai, 2020). These results initiated the development and validation of non-invasive, gamma sensory stimulation as a potential therapeutic for AD treatment. Design/Methods: Participants on AD spectrum were randomized to receive daily, one-hour, EEG-calibrated, noninvasive audio-visual stimulation, or sham stimulation in a 6-month clinical trial (Overture trial; NCT03556280) using Cognito Therapeutics medical device. Both safety (MRI, physical and neurological exams), and efficacy (AD cognitive and functional instruments, volumetric MRI) were assessed. Results: A total of 135 subjects were screened, 74 were randomized, and 53 completed the trial. The rate of AEs during the trial were roughly equivalent between groups. There were no unexpected serious treatment adverse events. Over the 6-month treatment period, changes in ADCS-ADL scores were significantly better in the treatment group compared to sham, indicating a 78% slowing in functional decline (P<0.0003). Similarly, the treatment group demonstrated a statistically significant 83% (p<0.013) reduction in cognitive decline, shown by changes in MMSE scores. The outcomes of MADCOMs, ADAS-cog14 and CDR-sb were not statistically different between groups. Quantitative MRI analysis revealed that whole brain volume loss in the treatment group demonstrated a significant, 72% reduction in brain atrophy (p<0.01) compared to sham group. Reduced lateral ventricle enlargement and diminished loss in cortical thickness in the occipital cortex have been also observed. MRI data demonstrated absence of ARIA in all subjects. Conclusions: Long-term, daily, self-administered, home-use of gamma sensory stimulation is both safe and well tolerated in AD subjects. Patients given gamma stimulation therapy maintained cognitive and functional abilities. Gamma sensory stimulation reduced brain atrophy, indicating potential disease-modifying effects in AD.