Most strategies for treating Alzheimer’s disease center on finding a drug that will reverse the disease pathology biochemically. Drugs, however, can be expensive and have side effects.
In 2016, the labs of Li-Huei Tsai, Emery Brown and Ed Boyden teamed up to try a completely different approach: After observing that gamma frequency (40Hz) brain wave power and synchrony is substantially weaker in Alzheimer’s model mice and may also be in patients, they experimented in mice with instilling the rhythms with completely non-invasive 40Hz flashes of visible light. In a paper in Nature in December 2016, they showed that the flashes had several beneficial effects:
The trio called this non-invasive, inexpensive potential treatment for neurodegeneration: GENUS, for Gamma ENtrainment Using Sensory stimuli. A 2019 study in Neuron showed that long-term GENUS light protected against neurodegeneration. In 2019 in Cell they showed that 40Hz sound stimulation works in mice, too, Both papers showed that GENUS preserved memory and cognitive performance. In 2023 the team followed up to show that tactile stimulation (40 Hz vibrations) also reduce Alzheimer's pathology and symptoms in mouse models. The following year in Nature, they identified a key mechanism of how GENUS helps the brain to clear amyloid proteins (see second video below): increased glymphatic fluid clearance. Essentially, increased 40Hz activity in VIP-expressing neurons increases release of a peptide that stimulates vascular pulsation and an increase in astrocyte opening up channels along the vasculature for cerebrospinal fluid flow from the glymphatic system. The fluid washes amyloid from brain tissue and drains through the meninges.
They have since begun testing GENUS in humans. In 2022 they published results of pilot Phase 1 and Phase 2A clinical studies showing that audio and visual GENUS was safe, well tolerated and successful in increasing 40Hz power and coherence around the brain. Moreover, treated participants showed reduced brain atrophy, improved sleep patterns and improvement on face-name association memory after three months compared to untreated controls. Tsai and Boyden also founded the company Cognito Therapeutics to accelerate this translational work. They are also studying whether non-invasive entrainment of rhythms can positively impact other diseases and partnering with engineers and designers to invent new modes for delivering the stimuli.
Above: A rendering of a microglia-like cell, stimulated to action by GENUS, absorbing amyloid plaques.