SUMMARY Non-invasive G amma EN trainment U sing S ensory stimuli (GENUS) at 40Hz reduced Alzheimer’s disease (AD) pathology, prevented cerebral atrophy and improved performance during behavioral testing in mouse models of AD. We report data from a safety study ( NCT04042922 ) and a randomized, placebo-controlled trial in participants with probable mild AD dementia after 3 months of one-hour daily 40Hz light and sound GENUS ( NCT04055376 ) to assess safety, compliance, entrainment and possible effects on brain structure, function, sleep and cognitive function. GENUS was well-tolerated and compliance was high in both groups. Electroencephalography recordings show that our GENUS device safely and effectively induced 40Hz entrainment in cognitively normal subjects and participants with mild AD. After 3 months of daily stimulation, participants with mild AD in the 40Hz GENUS group showed less ventricular enlargement and stabilization of the hippocampal size compared to the control group. Functional connectivity increased in both the default mode network and the medial visual network after 3 months of stimulation. Circadian rhythmicity also improved with GENUS. Compared to controls, the active group performed better on the face-name association delayed recall test. These results suggest that 40Hz GENUS can be used safely at home daily and shows favorable outcomes on cognitive function, daily rhythms, and structural and functional MRI biomarkers of AD-related degeneration. These results support further evaluation of GENUS in larger and longer clinical trials to evaluate its potential as a disease modifying therapeutic for Alzheimer’s disease.

Gamma Frequency Sensory Stimulation in Probable Mild Alzheimer’s Dementia Patients: Results of a Preliminary Clinical Trial