40Hz sensory gamma rhythm: A new hope in Alzheimer's treatment through enhanced brain clearance

In an exciting development in the fight against Alzheimer’s disease, researchers from the Massachusetts Institute of Technology (MIT) have unveiled findings that could pave the way for novel treatments.

Their study, recently published in Nature, demonstrates how specific brain rhythms, when stimulated through light and sound, can significantly reduce the progression of Alzheimer’s disease. The key to this breakthrough lies in the enhanced clearance of amyloid proteins from the brain, thanks to the activation of the brain’s glymphatic system, a critical waste-clearance pathway.

Alzheimer’s disease stands as one of the most formidable challenges in the field of neurodegenerative research. It is a progressive disorder characterized by the deterioration of memory and cognitive functions, profoundly impacting the lives of individuals and their families.

At the heart of Alzheimer’s pathology are two key players: amyloid-beta plaques and tau tangles. Amyloid-beta is a protein that can accumulate in the spaces between nerve cells, forming plaques that are believed to disrupt cell function.

Tau is a protein that stabilizes microtubules in neurons, but in Alzheimer’s, tau proteins become abnormal and form tangles inside the cells, leading to further neuronal dysfunction and cell death. These pathological markers not only contribute to the clinical symptoms of Alzheimer’s but also signify the complexity of developing effective treatments.

In recent years, research has explored innovative ways to mitigate the progression of Alzheimer’s disease, with a notable focus on non-invasive methods. Among these, sensory stimulation at a gamma frequency of 40 Hz has emerged as a promising approach. Previous studies, including those conducted at MIT and other institutions, have demonstrated that exposure to light flickering and sound clicking at this specific frequency can reduce amyloid levels in the brains of mouse models of Alzheimer’s.

These findings suggested that gamma stimulation could influence brain activity in a way that promotes the clearance of amyloid-beta, potentially offering a new avenue for treatment. However, the mechanisms underlying these effects remained largely unknown, prompting further investigation.

“Ever since we published our first results in 2016, people have asked me how does it work? Why 40 Hz? Why not some other frequency?” said study senior author Li-Huei Tsai, Picower Professor of Neuroscience and director of The Picower Institute and MIT’s Aging Brain Initiative. “These are indeed very important questions we have worked very hard in the lab to address.”

To initiate their investigation, the researchers employed a mouse model genetically engineered to exhibit Alzheimer’s-like characteristics, known as “5XFAD” mice. These mice carry mutations that lead to elevated levels of amyloid beta, mirroring the pathological hallmark of Alzheimer’s disease in humans.

The initial step involved replicating previous findings, confirming that exposure to 40 Hz sensory stimulation—specifically, light flickering and sound clicking at this frequency—indeed elevated gamma frequency neuronal activity in the brain and led to a reduction in amyloid levels. This foundational work set the stage for deeper inquiries into the underlying biological processes.

The researchers then turned their attention to the glymphatic system, a recently discovered network that facilitates the removal of waste from the brain, paralleling the lymphatic system in the rest of the body. They hypothesized that the glymphatic system might play a key role in the observed reduction of amyloid following gamma stimulation. Through experiments, they measured the flow of cerebrospinal fluid (CSF) within the brain’s tissue of mice subjected to 40 Hz stimulation, comparing these measurements to those from untreated control mice.

The results were striking: gamma-treated mice exhibited a significant increase in CSF flow through the brain tissue, as well as an enhanced rate of interstitial fluid exit, suggesting an active engagement of the glymphatic system in clearing amyloid proteins.

Delving further into the molecular mechanisms, the team explored the role of aquaporin-4 (AQP4) water channels located on astrocyte cells, which are crucial for the exchange of glymphatic fluid. By chemically blocking AQP4 function, they observed a prevention of amyloid reduction and cognitive improvement effects from gamma stimulation, highlighting the pivotal role of AQP4 and astrocytes in this process. Additionally, genetic techniques disrupting AQP4 confirmed its essential role in facilitating amyloid clearance through gamma-driven stimulation.

Another fascinating discovery emerged from examining the role of specific neurons and peptides in this process. The researchers found that gamma stimulation led to an increase in the production of certain peptides by a subset of neurons known as interneurons. Among these peptides, vasoactive intestinal peptide (VIP) stood out for its potential Alzheimer’s-fighting benefits.

Experiments revealed that increasing VIP in the brains of gamma-treated mice played a crucial role in mediating the glymphatic clearance of amyloid. Further, chemically shutting down VIP-expressing neurons negated the benefits of gamma stimulation, underscoring the importance of peptide signaling in this context.

The study’s findings illuminate a complex interplay between neuronal activity, peptide signaling, and the brain’s waste clearance systems, providing valuable insights into how sensory stimulation at a gamma frequency can influence the pathology of Alzheimer’s disease. The results suggest a promising new avenue for therapeutic intervention, highlighting the glymphatic system’s role in clearing amyloid proteins and offering a deeper understanding of the biological mechanisms that could be leveraged to combat neurodegenerative diseases.

The study, “Multisensory gamma stimulation promotes glymphatic clearance of amyloid,” was authored by Mitchell H. Murdock, Cheng-Yi Yang, Na Sun, Ping-Chieh Pao, Cristina Blanco-Duque, Martin C. Kahn, TaeHyun Kim, Nicolas S. Lavoie, Matheus B. Victor, Md Rezaul Islam, Fabiola Galiana, Noelle Leary, Sidney Wang, Adele Bubnys, Emily Ma, Leyla A. Akay, Madison Sneve, Yong Qian, Cuixin Lai, Michelle M. McCarthy, Nancy Kopell, Manolis Kellis, Kiryl D. Piatkevich, Edward S. Boyden, and Li-Huei Tsai.