Non-invasive Gamma ENtrainment Using Sensory stimulation (GENUS) at 40Hz reduces Alzheimer’s disease (AD) pathology such as amyloid and tau levels, prevents cerebral atrophy, and improves behavioral testing performance in mouse models of AD. Here, we report data from (1) a Phase 1 feasibility study (NCT04042922, ClinicalTrials.gov) in cognitively normal volunteers (n = 25), patients with mild AD dementia (n = 16), and patients with epilepsy who underwent intracranial electrode monitoring (n = 2) to assess safety and feasibility of a single brief GENUS session to induce entrainment and (2) a single-blinded, randomized, placebo-controlled Phase 2A pilot study (NCT04055376) in patients with mild probable AD dementia (n = 15) to assess safety, compliance, entrainment, and exploratory clinical outcomes after chronic daily 40Hz sensory stimulation for 3 months. Our Phase 1 study showed that 40Hz GENUS was safe and effectively induced entrainment in both cortical regions and other cortical and subcortical structures such as the hippocampus, amygdala, insula, and gyrus rectus. Our Phase 2A study demonstrated that chronic daily 40Hz light and sound GENUS was well-tolerated and that compliance was equally high in both the control and active groups, with participants equally inaccurate in guessing their group assignments prior to unblinding. Electroencephalography recordings show that our 40Hz GENUS device safely and effectively induced 40Hz entrainment in participants with mild AD dementia. After 3 months of daily stimulation, the group receiving 40Hz stimulation showed (i) lesser ventricular dilation and hippocampal atrophy, (ii) increased functional connectivity in the default mode network as well as with the medial visual network, (iii) better performance on the face-name association delayed recall test, and (iv) improved measures of daily activity rhythmicity compared to the control group. These results support further evaluation of GENUS in a pivotal clinical trial to evaluate its potential as a novel disease-modifying therapeutic for patients with AD.

Non-invasive Gamma ENtrainment Using Sensory stimulation (GENUS) at 40Hz reduced Alzheimers disease (AD) pathology such as amyloid and tau levels, prevented cerebral atrophy and improved performance during behavioral testing in mouse models of AD. We report data from a randomized, placebo-controlled trial (n = 15) in volunteers with probable mild AD after 4 months of one-hour daily 40Hz sensory stimulation (NCT 04055376) to assess safety, compliance, entrainment and possible effects on brain structure, function, sleep activity and cognitive function. 40Hz light and sound GENUS was well-tolerated and compliance was high in both groups. Electroencephalography recordings show that our novel 40Hz GENUS device safely and effectively induced 40Hz entrainment in participants with mild AD. After 3 months of daily stimulation, the 40Hz GENUS group showed reduced ventricular dilation and stabilization of the hippocampal size compared to the control group. Functional connectivity was found to improve in the default mode network as well as with the medial visual network after 3 months of stimulation. Furthermore, actigraphy recordings show that circadian rhythmicity also improved with 40Hz stimulation. 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, structure 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 novel disease modifying therapeutic for Alzheimers dementia.

Brain oscillations underlie the function of our brains, dictating how we both think and react to the world around us. The synchronous activity of neurons generates these rhythms, which allow different parts of the brain to communicate and orchestrate responses to internal and external stimuli. Perturbations of cognitive rhythms and the underlying oscillator neurons that synchronize different parts of the brain contribute to the pathophysiology of diseases including Alzheimer’s disease, (AD), Parkinson’s disease (PD), epilepsy and other diseases of rhythm that have been studied extensively by Gyorgy Buzsaki. In this review, we discuss how neurologists manipulate brain oscillations with neuromodulation to treat diseases and how this can be leveraged to improve cognition and pathology underlying AD. While multiple modalities of neuromodulation are currently clinically indicated for some disorders, nothing is yet approved for improving memory in AD. Recent investigations into novel methods of neuromodulation show potential for improving cognition in memory disorders. Here, we demonstrate that neuronal stimulation using audiovisual sensory stimulation that generated 40‐HZ gamma waves reduced AD‐specific pathology and improved performance in behavioural tests in mouse models of AD, making this new mode of neuromodulation a promising new avenue for developing a new therapeutic intervention for the treatment of dementia.