Using LED lights flickering at a specific frequency, MIT researchers have shown that they can substantially reduce the beta amyloid plaques seen in Alzheimer’s disease, in the visual cortex of mice.

This treatment appears to work by inducing brain waves known as gamma oscillations, which the researchers discovered help the brain suppress beta amyloid production and invigorate cells responsible for destroying the plaques.

Further research will be needed to determine if a similar approach could help Alzheimer’s patients, says Li-Huei Tsai, the Picower Professor of Neuroscience, director of MIT’s Picower Institute for Learning and Memory, and senior author of the study, which appears in the Dec. 7 online edition of Nature.

Researchers in Li-Huei Tsai's laboratory at the Picower Institute for Learning and Memory have shown that disrupted gamma waves in the brains of mice with Alzheimer’s disease can be corrected by a unique non-invasive technique using flickering light. (Photo courtesy of Bryce Vickmark)

“It’s a big ‘if,’ because so many things have been shown to work in mice, only to fail in humans,” Tsai says. “But if humans behave similarly to mice in response to this treatment, I would say the potential is just enormous, because it’s so noninvasive, and it’s so accessible.”

Tsai and Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at the MIT Media Lab and the McGovern Institute for Brain Research, who is also an author of the Nature paper, have started a company called Cognito Therapeutics to pursue tests in humans. The paper’s lead authors are graduate student Hannah Iaccarino and Media Lab research affiliate Annabelle Singer.

“This important announcement may herald a breakthrough in the understanding and treatment of Alzheimer's disease, a terrible affliction affecting millions of people and their families around the world,” says Michael Sipser, dean of MIT’s School of Science. “Our MIT scientists have opened the door to an entirely new direction of research on this brain disorder and the mechanisms that may cause or prevent it. I find it extremely exciting.”

Researchers in Li-Huei Tsai's laboratory at the Picower Institute for Learning and Memory have shown that disrupted gamma waves in the brains of mice with Alzheimer’s disease can be corrected by a unique non-invasive technique using flickering light.

Video: The Picower Institute for Learning and Memory

Brain wave stimulation

Alzheimer’s disease, which affects more than 5 million people in the United States, is characterized by beta amyloid plaques that are suspected to be harmful to brain cells and to interfere with normal brain function. Previous studies have hinted that Alzheimer’s patients also have impaired gamma oscillations. These brain waves, which range from 25 to 80 hertz (cycles per second), are believed to contribute to normal brain functions such as attention, perception, and memory.

In a study of mice that were genetically programmed to develop Alzheimer’s but did not yet show any plaque accumulation or behavioral symptoms, Tsai and her colleagues found impaired gamma oscillations during patterns of activity that are essential for learning and memory while running a maze.

Next, the researchers stimulated gamma oscillations at 40 hertz in a brain region called the hippocampus, which is critical in memory formation and retrieval. These initial studies relied on a technique known as optogenetics, co-pioneered by Boyden, which allows scientists to control the activity of genetically modified neurons by shining light on them. Using this approach, the researchers stimulated certain brain cells known as interneurons, which then synchronize the gamma activity of excitatory neurons.

After an hour of stimulation at 40 hertz, the researchers found a 40 to 50 percent reduction in the levels of beta amyloid proteins in the hippocampus. Stimulation at other frequencies, ranging from 20 to 80 hertz, did not produce this decline.

Tsai and colleagues then began to wonder if less-invasive techniques might achieve the same effect. Tsai and Emery Brown, the Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience, a member of the Picower Institute, and an author of the paper, came up with the idea of using an external stimulus — in this case, light — to drive gamma oscillations in the brain. The researchers built a simple device consisting of a strip of LEDs that can be programmed to flicker at different frequencies.

Using this device, the researchers found that an hour of exposure to light flickering at 40 hertz enhanced gamma oscillations and reduced beta amyloid levels by half in the visual cortex of mice in the very early stages of Alzheimer’s. However, the proteins returned to their original levels within 24 hours.

The researchers then investigated whether a longer course of treatment could reduce amyloid plaques in mice with more advanced accumulation of amyloid plaques. After treating the mice for an hour a day for seven days, both plaques and free-floating amyloid were markedly reduced. The researchers are now trying to determine how long these effects last.

Furthermore, the researchers found that gamma rhythms also reduced another hallmark of Alzheimer’s disease: the abnormally modified Tau protein, which can form tangles in the brain.

“What this study does, in a very carefully designed and well-executed way, is show that gamma oscillations, which we have known for a long time are linked to cognitive function, play a critical role in the capacity of the brain to clean up deposits,” says Alvaro Pascual-Leone, a professor of neurology at Harvard Medical School who was not involved in the research. “That’s remarkable and surprising, and it opens up the exciting prospect of possible translation to application in humans.”

Tsai’s lab is now studying whether light can drive gamma oscillations in brain regions beyond the visual cortex, and preliminary data suggest that this is possible. They are also investigating whether the reduction in amyloid plaques has any effects on the behavioral symptoms of their Alzheimer’s mouse models, and whether this technique could affect other neurological disorders that involve impaired gamma oscillations.

Two modes of action

The researchers also performed studies to try to figure out how gamma oscillations exert their effects. They found that after gamma stimulation, the process for beta amyloid generation is less active. Gamma oscillations also improved the brain’s ability to clear out beta amyloid proteins, which is normally the job of immune cells known as microglia.

“They take up toxic materials and cell debris, clean up the environment, and keep neurons healthy,” Tsai says.

In Alzheimer’s patients, microglia cells become very inflammatory and secrete toxic chemicals that make other brain cells more sick. However, when gamma oscillations were boosted in mice, their microglia underwent morphological changes and became more active in clearing away the beta amyloid proteins.

“The bottom line is, enhancing gamma oscillations in the brain can do at least two things to reduced amyloid load. One is to reduce beta amyloid production from neurons. And second is to enhance the clearance of amyloids by microglia,” Tsai says.

The researchers also sequenced messenger RNA from the brains of the treated mice and found that hundreds of genes were over- or underexpressed, and they are now investigating the possible impact of those variations on Alzheimer’s disease.

The research was funded by the JPB Foundation, the Cameron Hayden Lord Foundation, a Barbara J. Weedon Fellowship, the New York Stem Cell Foundation Robertson Award, the National Institutes of Health, the Belfer Neurodegeneration Consortium, and the Halis Family Foundation.

MIT transfers LED treatment patent to startup Cognito Therapeutics

Medical startup Cognito Therapeutics, based jointly in Cambridge and San Francisco, said that it will be licensing the intellectual property from the research to market a LED light treatment system for Alzheimers, reported The Boston Globe.

This presents a huge opportunity, said Daniel Burnett, the Chief Technology of Cognito.

“There’s a dire need for Alzheimer’s therapies, and there’s little we can do about the disease right now,” said Burnett. “If we can develop something that can slow the decline of patients with very little side effects that could be revolutionary.”

Head of the research team Researcher Tsai, who is also a co-founder of

A medical technology startup called Cognito Therapeutics Inc., based jointly in Cambridge and San Francisco, said Wednesday that it’s licensing intellectual property stemming from the MIT research in an effort to market a system of LED lighting to treat Alzheimer’s.

“This is a monstrous opportunity,” said Daniel Burnett, the San Francisco-based chief technology officer of venture-backed Cognito. “There’s a dire need for Alzheimer’s therapies, and there’s little we can do about the disease right now. If we can develop something that can slow the decline of patients with very little side effects, that could be revolutionary.”

Scientests at Picower Institute developed a similar treatment method of using LEDs flickered at a precise frequency to substantially reduce beta amyloid plaque in the visual cortex in the brains of mice with Alzheimer’s to restore gamma rhythms that were altered by the disease.

MIT research team leader Tsai is a scientific co-founder of Cognito, said the new company aims to move its treatment into clinical trials quickly to determine whether the same mechanisms that work in mice are also applicable in humans when it comes to suppressing the production of beta amyloid and activating plaque-destroying cells.

The effects on humans are “unknown” so far, Tsai said.

“I don’t want to make a fool of myself by saying it’s going to work in humans,” she said. “There’s so many innovations in the past that seemed to work in mice that failed in humans.”

Cognito was launched in early 2016 with financing from Morningside Venture, an arm of the Morningside Group headquartered in Hong Kong, said Burnett.

About half dozen Cognito employees are preparing the lighting system for clinical trials in humans, while two other employees including chief executive Jason Dinges, work in Cambidge where the company’s business operations will be based.

The startup is looking into hiring more employees in early 2017, and will have a staff of 15 to 25 employees in U.S. by late 2017.

 “We work at light speed to get quality management set up, make sure we’re on the right track, and initiate clinical trials with minimal delay,” Burnett said.

 “…[I]f humans behave similarly to mice in response to this treatment, I would say the potential is just enormous, because it’s so noninvasive, and it’s so accessible,” says Li-Huei Tsai, the Picower Professor of Neuroscience, when describing a new treatment for Alzheimer’s disease.

Photo: Bryce Vickmark

Researchers in Li-Huei Tsai's laboratory at the Picower Institute for Learning and Memory have shown that disrupted gamma waves in the brains of mice with Alzheimer’s disease can be corrected by a unique non-invasive technique using flickering light.