AbstractBackgroundNon‐invasive gamma frequency light and sound stimulation at 40Hz reduced Alzheimer’s disease (AD) pathology and improved performance during behavioral testing in mouse models of AD (Iaccarino et al., Nature, 2016; Martorell et al., Cell, 2019; Adaikkan et al., Neuron, 2019). Sensory stimulation inducing 40Hz entrainment reduced amyloid and hyperphosphorylated tau burden and prevented brain atrophy in different mouse models of AD. Performance on tasks testing short‐term memory and spatial learning improved after 6 weeks of daily 40Hz stimulation. We therefore hypothesized that translation of gamma entrainment with light and sound can be used as a disease‐modifying therapeutic for AD.MethodsWe conducted a placebo‐controlled, randomized control trial (n = 15) in volunteers with probable mild AD to use our light and sound device at home for one hour daily (NCT 04042922). Control devices delivered constant light and white noise while devices with the active setting produced patterned and synchronized light and sound at 40Hz. Electroencephalogram (EEG) was used to evaluate for safety and entrainment when using the 40Hz stimulation. Weekly phone questionnaires were used to assess safety. Magnetic resonance imaging was used to evaluate brain structure and actigraphy was used to record sleep. Face‐name association delayed recall was done to assess changes in cognition.ResultsWe report interim results after 3 months of daily 40Hz stimulation. Mild AD patients were highly compliant with usage in both the control and active groups. EEG data show that our novel light and sound device safely and effectively induced 40Hz entrainment in subjects with mild AD. After 3 months of daily stimulation, 40Hz entrainment prevents both hippocampal atrophy and ventricular enlargement and the extent of ventricular change differs between groups (p = 0.034, p = 0.024, p = 0.043, respectively). Circadian rhythmicity also improved with 40Hz stimulation (p = 0.03). Performance on the face‐name association delayed recall test improved in accuracy (p = 0.004).ConclusionsGamma frequency light and sound stimulation can be used safely daily for 3 months and prevents AD‐related degeneration. Induced entrainment using sensory stimulation at 40Hz shows promise as a novel disease modifying therapeutic for Alzheimer’s dementia.