40Hz sensory stimulation induces gamma entrainment and affects brain structure, sleep and cognition in patients with Alzheimer's dementia

Chan, D.; Suk, H.-J.; Jackson, B. L.; Milman, N. P.; Stark, D.; Klerman, E. B.; Kitchener, E.; Fernandez Avalos, V. S.; Banerjee, A.; Beach, S. D.; Blanchard, J.; Stearns, C.; Boes, A.; Uitermarkt, B.; Gander, P.; Howard, M.; Sternberg, E. J.; Nieto-Castanon, A.; Anteraper, S.; Whitfield-Gabrieli, S.; Brown, E. N.; Boyden, E. S.; Dickerson, B. C.; Tsai, L.-H.

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.