Gamma Frequency Sensory Stimulation as a Potential Therapy for Alzheimer Disease

Li-Huei Tsai, PhD

Alzheimer disease (AD) can be confirmed through the reduction of fast brain oscillations in the gamma. Several recent studies have revealed that using gamma oscillations through sensory stimulation at 40 Hz may potentially impact AD-related cognitive decline and neuropathological processes.¹ Hence, using tools such as Gamma Entrainment Using Sensory stimulation (GENUS) may be a promising therapeutic approach for patients with AD.

Senior author Li-Huei Tsai, PhD, director, the Picower Institute for Learning and Memory at Massachusetts Institute of Technology, and colleagues recently published a study in PLoS One on a phase 1 feasibility study (NCT04042922) and a single-blinded, randomized, placebo-controlled phase 2a pilot study (NCT04055376).² The phase 1 study demonstrated that 40 Hz GENUS was a safe and effective treatment that induced entrainment in both cortical regions and other subcortical structures of the brain. Additionally, the phase 2A study showed chronic daily 40Hz light and sound GENUS were well-tolerated.

In a recent interview with NeurologyLive^®, Tsai sat down to talk about one of her research studies on gamma frequency sensory stimulation in mild probable AD. Based on the findings of the study, she explained how gamma frequency works and the current knowledge of using it as a tool for patients with AD. Tsai, who also serves as Picower professor of neuroscience in the department of brain and cognitive sciences, spoke more on the results, including the unexpected findings and the focus for future investigations.

NeurologyLive^®: How does gamma frequency work and what do we know about it as of now?

Li-Huei Tsai, PhD: We found that gamma frequency changes the morphology, gene expression, and function of microglia. It also increases the diameter of the capillaries, likely resulting in increased brain waste clearance. Ongoing work suggests that gamma frequency impacts other cell types in the brain and beyond. Therefore, increased gamma power has a whole systems level effect which renders brain to be in a healthier state.

What these results mean for patients with Alzheimer disease?

Many proposed Alzheimer disease therapies have appeared highly effective in mice but have not translated successfully to humans. Early stage testing of safety, feasibility and efficacy in humans is therefore essential to determine whether 40 Hz sensory stimulation could be a clinically meaningful treatment. In our phase 1 study, we found that 40Hz sensory stimulation was safe for human participants with no major adverse events. The stimulation successfully increased 40 Hz rhythm power, and synchrony was observed in wide areas of the brain in young and older healthy participants as well as in patients with early stage Alzheimer disease.

In our phase 2a study, which was blinded, randomized and controlled, neither treated nor control volunteers reported serious adverse events. Both groups used their devices at home 90% of the time. The 8 volunteers treated with 40 Hz stimulation experienced several beneficial effects that reached statistical significance compared to the 7 volunteers in the control condition. Control participants exhibited two signs of brain atrophy as expected with disease progression; reduced volume of the hippocampus and increased volume of ventricles.

Treated patients did not experience significant changes in these measures. Treated patients also exhibited better connectivity across brain regions involved in the brain’s default mode and medial visual networks. Treated patients also exhibited more consistent sleep patterns than controls. Neither the treatment nor control groups showed any differences after just 3 months on most cognitive tests, but the treatment group did perform significantly better on a face-name association test, a memory task with a strong visual component.

While we were encouraged to see some significant positive effects on the brain and behavior, we are interpreting them cautiously given our study’s small sample size and brief duration. These results are not sufficient evidence of efficacy, but we believe they clearly support proceeding with more extensive study of 40 Hz sensory stimulation as a potential non-invasive therapeutic for Alzheimer’s disease.

Was there anything surprising from the results?

We were pleasantly surprised to see some significant effects even by our 3-month follow-up timepoint. Unfortunately, the very negative surprise of the onset of the COVID-19 pandemic prevented us from being able to conduct longer-term follow-ups. Overall, though, we found that the safety profile and early data on efficacy was consistent with what we hoped we’d see based on the results in mouse models.

What needs to be further investigated?

To be certain, larger, longer-term follow-up studies are needed before anything can be said with authority about clinical efficacy. Cognito Therapeutics, an MIT spin-off company that I co-founded with Ed Boyden, has launched phase 3 trials that should help us learn more.

Beyond that, at MIT, we are planning other studies including one to test whether 40 Hz sensory stimulation can help prevent AD onset in high-risk patients. And in the lab, we continue to investigate the underlying cellular and molecular mechanisms that appear to mediate 40 Hz sensory stimulation’s effects on brain health.

Transcript edited for clarity.

REFERENCES
1. Manippa V, Palmisano A, Filardi M, et al. An update on the use of gamma (multi)sensory stimulation for Alzheimer's disease treatment. Front Aging Neurosci. 2022;14:1095081. Published 2022 Dec 15. doi:10.3389/fnagi.2022.1095081
2. Chan D, Suk HJ, Jackson BL, et al. Gamma frequency sensory stimulation in mild probable Alzheimer's dementia patients: Results of feasibility and pilot studies. PLoS One. 2022;17(12):e0278412. Published 2022 Dec 1. doi:10.1371/journal.pone.0278412