This article is part of a small series on 40-hertz brain stimulation for the treatment of neurodegenerative diseases, including Alzheimer’s and Parkinson’s. The first in the series can be read here, and the second, here. It is also part of a larger, ongoing series on aging and longevity.

Alzheimer’s disease and other dementias are the most common age-associated neurological disorders. By 2030, 78 million people are expected to be living with impaired cognition caused by dementia. Stimulation of the brain with 40-hertz frequencies has proved a promising avenue for treatment, with a handful of successful early trials. But why the treatment works, at the molecular and cellular levels, has remained poorly understood. A new study indicates that 40-hertz stimulation helps increase the activity of the “glymphatic” system, which is integral to the clearance of metabolic waste, including the build-up of misfolded proteins associated with Alzheimer’s disease. 

Flashing Lights Protect Against Alzheimer’s Disease? 

Our ability to think, recall, and abstract is central to everything we do. As we age, many of these faculties begin to diminish — our brains can no longer keep up the usual pace. In fact, age is the most significant risk factor for the development of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. An estimated 6.7 million Americans age 65 and older were living with Alzheimer’s in 2023. And this number is steadily growing. Still, treatment options remain scarce. The few that are available, like Leqembi, are often cost-prohibitive, with an annual price tag in the tens of thousands. 

Back in 2016, a group of researchers at the Massachusetts Institute of Technology (MIT) began exploring a new and fairly unusual strategy for the treatment of Alzheimer’s disease: stimulating the brain using lights and sounds set to a 40-hertz frequency. Why? 

Brain functions are regulated by the communication of a synchronized network of brain cells called neurons. These send signals to one another, and across the nervous system, by way of electrical impulses. Neuronal activity of this kind follows certain patterns or rhythms, more commonly known as “brain waves”. When you get an electroencephalography (EEG), for example, doctors are essentially looking at the rhythm of your brain’s tides. Well, gamma waves —characterized by an oscillation pattern of 40 cycles, or hertz, per second— are some of the fastest brain waves, intimately linked to the connectivity of different brain regions. They are thought to play an active role in both memory and sustained attention.

Led by Dr. Li-Huei Tsai, the team of scientists at MIT’s Picower Institute noticed that gamma waves were decreased in mice suffering from Alzheimer’s disease. This was especially evident in the hippocampus, a part of the brain long understood to be critical for memory and learning. The results piqued their interest; would artificially boosting gamma-wave activity help fight off cognitive decline? Indeed, exposing mice to a light flickering at 40 hertz helped cut down amyloid plaques, a hallmark of the disease, by almost half. 

Since then, the Tsai Laboratory has gone on to perform many follow-up studies, all of which indicate that lights flashing at 40 cycles per second, or sounds clicking at the same frequency, can reduce the symptoms of Alzheimer’s disease in mice. Two early-stage human studies helped confirm the safety of the approach and suggest that the same benefits seen in mice may be available to us. They are now recruiting for a large biomarker study called HOPE, the results of which should be available by 2025. 

But through all this, one thing remained frustratingly unclear: how, and why, does gamma stimulation stave off cognitive decline? What are the mechanisms at the biological and molecular levels? 

The Brain’s Very Own Plumbing System 

A fresh round of experiments by the Tsai Laboratory has offered some answers. Published in Nature, the findings suggest that 40-hertz stimulation works by boosting a recently discovered “plumbing system” in the brain, called the glymphatic system, which flushes out metabolic waste, including the infamous amyloid plaques associated with Alzheimer’s disease. 

Our body is constantly producing waste products: substances that are left over from metabolic processes, such as protein synthesis, but cannot be put to any other use. If these waste products are left to pile up, they begin to have toxic effects on the surrounding tissues. Not good. 

In most regions of the body, the responsibility for preventing this kind of clogging falls on the lymphatic system. This system is made up of a large network of “pipes”, called lymph vessels, filled with a fluid called lymph. Cells excrete waste products into interstitial fluid, which surrounds and separates cells. This fluid, filled with all the cellular “sewage”, moves into the lymph vessels, where it merges with the lymph and is carried away to be filtered, broken down, and eventually removed — think urination, or well, the other one.  

But the central nervous system, despite being an especially sensitive system, does not contain any lymphatic structures. Still, it is somehow very efficient at clearing waste. This left researchers scratching their heads. If the lymphatic system doesn’t extend to the brain, how are waste products and debris being removed? In 2012, a group of Danish scientists discovered what they dubbed the “glymphatic” system. Basically, the brain’s very own, custom-made lymphatic system. 

The glymphatic system is composed of tiny, specialized channels that follow along the blood vessels of the brain, giving cerebrospinal fluid —a colorless fluid that surrounds the brain and provides nutrients— quick and easy access to all areas. Think of pipes in a house transporting water to wherever it’s needed. Traveling along these channels, cerebrospinal fluid is flushed into the “meaty” tissue of the brain, where it mixes with soiled interstitial fluid. The cerebrospinal fluid picks up all of the waste products in the spaces between neurons before being flushed out again through the same channels, leaving behind clean interstitial fluid. The waste products are then sent to the lymph nodes in the neck for filtering and disposal. 

How Gamma Waves Protect The Brain

To test whether 40-hertz stimulation influences the glymphatic system, Tsai and her colleagues checked if the intervention was linked to any changes in the flow of fluids in the brain. They found that mice treated with gamma stimulation had more cerebrospinal fluid in their brain tissue compared to untreated mice. They also noticed that the fluid left the brain more quickly in the treated mice, possibly due to a physical enlargement of the special glymphatic channels. Finally, the lymph nodes in the necks of the mice that received 40-hertz stimulation were chock full of amyloid beta compared to those of the control group, suggesting that the harmful protein had been successfully drained out of the brain.

One likely explanation for these changes can be traced to a protein called aquaporin 4. This is a water-channel protein, meaning it helps direct fluids through cell membranes. The “feet” of astrocytes, a special kind of brain cell, are covered by aquaporin 4, allowing them to mediate glymphatic fluid exchange. The researchers noticed that blocking the protein, either chemically or genetically, also blocks the benefits of the 40-hertz brain stimulation, indicating that it plays a crucial role in the benefits associated with the treatment. 

Another potential explanation for the effectiveness of 40-hertz stimulation is the discovery that interneurons —a subset of neurons— produce certain peptides in far greater quantities following treatment. This includes a peptide known as vasoactive intestinal polypeptide (VIP), which is understood to have Alzehimer’s-busting effects and is associated with the regulation of blood flow and glymphatic clearance. As with aquaporin 4, blocking the expression of vasoactive intestinal polypeptide simultaneously blocked the clearance of amyloid beta; the effectiveness of the gamma stimulation fell apart.

Implications and Takeaways

This study represents another important step toward understanding the healing potential of 40-hertz light and sound stimulation. Whereas multiple mouse studies and a small number of human studies have supported the efficacy of the approach, none of them have explained how it works. Now, researchers at the Tsai Laboratory have managed to provide a plausible answer: gamma wave treatment improves the efficacy of the brain’s waste management system. This helps clear up accumulated debris and proteins which, if left unattended, would cause damage. 

2025 will bring with it the results of the team’s latest large-scale human trial. If all goes well, we may soon have a non-invasive and affordable treatment option for early-stage Alzheimer’s disease. Compared to our current options —essentially none— this would represent a massive leap forward.