In the decade since researchers at MIT first began exploring how brain waves might be harnessed to combat Alzheimer’s disease, a compelling body of evidence has emerged suggesting that a specific frequency of neural activity could offer new hope for patients and their families.
A new review published February 28 in PLOS Biology highlights how stimulating the brain at 40 hertz—a specific frequency in the gamma range—has demonstrated remarkable effects in both animal models and early human trials, offering a potentially groundbreaking approach that doesn’t rely on pharmaceutical interventions.
“As we’ve made all our observations, many other people in the field have published results that are very consistent,” said Li-Huei Tsai, Picower Professor at MIT and director of MIT’s Aging Brain Initiative, who co-authored the review with postdoc Jung Park. “People have used many different ways to induce gamma including sensory stimulation, transcranial alternating current stimulation or transcranial magnetic stimulation, but the key is delivering stimulation at 40 Hz. They all see beneficial effects.”
The technique, dubbed GENUS (Gamma ENtrainment Using Sensory stimuli), uses flickering lights, sound pulses, or tactile vibrations delivered at 40 cycles per second to induce the brain to oscillate at this same frequency. While the approach might sound surprisingly simple, the results suggest it produces complex biological responses that collectively combat various aspects of Alzheimer’s pathology.
A Challenge Requiring New Approaches
Alzheimer’s disease affects millions worldwide, with limited effective treatment options available despite decades of research. Traditional approaches have focused on managing symptoms or targeting specific disease markers like amyloid plaques and tau tangles with modest results.
Recent FDA-approved drugs such as aducanumab and lecanemab have shown the ability to clear amyloid plaques and slow cognitive decline by 27-35% after 18 months of treatment. However, these medications come with significant drawbacks, including high costs and potentially serious side effects such as brain swelling and bleeding in up to 40% of patients treated with aducanumab.
“The complexity of AD, in which multiple brain regions, circuits, cell types, and molecular pathways are compromised, means that targeting a single mechanism often falls short of delivering comprehensive benefits,” the researchers note in their review, highlighting why multi-faceted approaches like gamma stimulation might offer particular advantages.
From Mouse to Human
The journey began in 2016 when Tsai’s team published findings in Nature showing that exposing mice to light flickering at 40 hertz reduced levels of amyloid beta, a protein associated with Alzheimer’s disease. Subsequent studies demonstrated that the approach also worked with sound and tactile stimulation, with effects extending beyond the initially targeted brain regions.
Perhaps most importantly, these laboratory findings appear to be translating to humans. Early clinical studies at MIT and Cognito Therapeutics, a company spun off from this research, have shown promising results.
“In an early clinical trial, three months of daily treatment reduced brain atrophy—including in the hippocampus—and strengthened functional connectivity as measured by synchronization across brain regions. Patients also showed promising cognitive improvements,” Park and Tsai report in their review.
Cognito Therapeutics has developed a medical device delivering audiovisual stimulation that has been deemed safe and well-tolerated by Alzheimer’s patients. Results from daily one-hour treatments for six months showed a 69% reduction in brain volume loss, including reduced atrophy in the corpus callosum, a brain region critical for communication between the two hemispheres. The company has received FDA approval to conduct Phase III clinical trials with their device.
Understanding the Mechanism
What makes the gamma stimulation approach particularly intriguing is its multifaceted effects on brain biology. Researchers are beginning to understand how 40-hertz oscillations produce these benefits, with recent findings pointing to several mechanisms.
One pathway involves the brain’s waste-clearing system. Last year, Tsai’s team reported in Nature that “40-hertz audio and visual stimulation induced interneurons in mice to increase release of the peptide VIP, prompting increased clearance of amyloid from brain tissue via the brain’s glymphatic ‘plumbing’ system.”
A team in China independently corroborated in 2024 that 40-hertz sensory stimulation increases glymphatic fluid flows in mice, strengthening the evidence for this mechanism.
The stimulation also appears to alter the behavior of microglia (the brain’s immune cells), preserve neurons and synapses, and improve blood flow in the brain—producing a coordinated response that addresses multiple aspects of the disease simultaneously.
Beyond Alzheimer’s
The comprehensive nature of gamma stimulation’s effects suggests it might benefit other neurological conditions. Studies have shown potential applications for Parkinson’s disease, stroke recovery, epilepsy, anxiety, and even the cognitive side effects of chemotherapy.
Researchers at MIT demonstrated that audiovisual gamma stimulation protected mice from chemotherapy-induced impairments such as decreased brain volume, DNA damage, inflammation, and cognitive deficits. In a mouse model of multiple sclerosis, the treatment mitigated against demyelination and preserved the functional integrity of connections linking the two brain hemispheres.
“The more we understand the mechanisms, the more we will have good ideas about how to further optimize the treatment,” Tsai said. “And the more we understand its action and the circuits it affects, the more we will know beyond Alzheimer’s disease what other neurological disorders will benefit from this.”
Remaining Questions
Despite the encouraging progress, important questions remain. Researchers are still working to fully understand the cellular and molecular changes triggered by gamma stimulation. The MIT team is investigating other neuropeptide and neuromodulatory systems to better understand the cascade of events linking sensory stimulation to the observed cellular responses.
Additionally, methodological variability across different research groups presents challenges. Some labs use portable monitors with speakers while many larger clinical trials use wearable headsets to deliver audiovisual stimuli. There are also differences in the intensity of the stimuli and the specific wavelengths of light used.
Patient compliance poses another potential hurdle. Unlike medications that can be simply swallowed or administered by healthcare professionals, gamma stimulation currently requires patients to self-administer a one-hour daily protocol, which could affect consistent and correct usage.
A New Era of Treatment
Despite these challenges, the field of non-invasive sensory stimulation for neurological conditions is gaining momentum, with multiple research groups contributing findings that support the therapeutic potential of gamma entrainment.
For the millions affected by Alzheimer’s disease worldwide, these advances offer a promising new direction that contrasts with the limited success of traditional pharmaceutical approaches. The non-invasive nature of the treatment, combined with its apparent safety profile and the absence of serious side effects, makes it particularly attractive.
“After decades of limited progress, advances in neurotechnology have ushered in a new era in the treatment of AD,” Park and Tsai conclude in their review. “The advent of non-invasive 40-hertz sensory stimulation treatment has brought renewed optimism to patients, caregivers, and researchers alike.”
As Cognito Therapeutics continues its pivotal Phase III clinical trial and researchers across the world further explore the potential of gamma stimulation, the next decade may bring significant advances for those affected by this devastating condition. While not a cure, this approach offers a novel strategy in the ongoing battle against neurodegenerative disease—one that harnesses the brain’s own rhythms to combat its decline.
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