Dr. Paul Solomon has seen more than his fair share of intriguing ideas for treating Alzheimer’s disease, some of them better than others. Over the past few decades, the neuroscientist and neuropsychologist has led more than 200 clinical trials looking for ways to slow the memory-robbing disease and other dementia-related conditions.
“Not a month goes by where someone doesn’t come to visit us and tell us about the next greatest thing. Most of them are not the next greatest thing,” said Solomon, who is the founder and clinical director of the Boston Center for Memory in Newton. Although most of those studies have failed, he hopes one of the latest efforts may turn out differently.
Last month, Solomon began enrolling patients in a large clinical trial that will test whether an experimental device built by Cambridge biotech Cognito Therapeutics can stall Alzheimer’s. About 500 patients at 50 sites around the country will get a headset to wear at home for an hour a day that uses light and sound frequencies to reset brainwaves.
The technique, known as gamma wave therapy, sounds like science fiction, or a scam, or just plain kooky. But it is based on research by MIT scientists, and the startup announced Wednesday that it’s raised $73 million to fund the clinical study required for federal regulators to greenlight the device.
“Most people still think this is an oddball, but we stand behind our due diligence,” said Helen H. Liang, founder and managing partner of FoundersX Fund Ventures, a technology-focused venture capital firm based in California and Cambridge that led Cognito’s new financing. “We are not high risk-takers. We think there is a strong science behind it.”
Cognito chief executive Brent Vaughan expects the new study to wrap up in 2025. Potentially, he said, the company could submit its device to the FDA and gain approval by the end of that year.
Gamma waves are a little-studied electrical signal that brain cells make when we are learning or concentrating. Although neuroscientists have long known that these brainwaves are sluggish or missing in people with Alzheimer’s, there were few efforts to do anything about it.
That changed in 2016 when a team led by MIT neuroscientists Li-Huei Tsai and Ed Boyden figured out how to trigger gamma waves in mice, first using a complex molecular technique known as optogenetics, and later with simple light and sound stimulation. To their amazement, the gamma waves cleared the mouse brains of sticky clumps of proteins called amyloid plaques, known to accumulate in Alzheimer’s patients.
“It was the most surprising result I’ve ever got in my life,” said Tsai, who is the director of the Picower Institute for Learning and Memory at MIT. “When we published our first paper, most people said, ‘I don’t believe it. This is too good to be true. How can something this simple have this kind of effect?’”
Tsai and Boyden cofounded Cognito to translate their bewildering results from mice into humans. The company launched the same day that their mice study was published in the prestigious scientific journal Nature in December 2016. Both scientists still serve as scientific advisors to the startup.
The company approached Solomon before the COVID pandemic to see if he would lead a small study assessing the safety of the approach, and whether patients would tolerate using a device that flickered light into their eyes for an hour a day. Solomon had heard of Tsai and Boyden’s research, so he agreed to run the study and found that the device increased gamma waves with few to no side effects in most participants.
“It’s a very fast flicker. They’ll see a white light,” and not a strobe effect, Vaughan said.
Cognito soon began testing its device in an intermediate study, and released the preliminary results in early 2021. The company said that 33 people who used it daily for six months saw their cognitive decline slow by 83 percent and their functional decline slow by 84 percent compared with 19 people who got a placebo device. “We made Alzheimer’s patients look like non-Alzheimer’s patients,” he said.
Vaughan acknowledges that his claim is extraordinary. “But that’s what the data shows,” he said. He also noted that the treatment did not clear amyloid plaques from patient brains like it did in mice — something that’s been a major holdup for some prospective investors.
“The results sound amazing, but there have been other Phase 2 studies that have shown promise and didn’t end up working in a Phase 3 study,” said Dr. Andrew E. Budson, chief of cognitive and behavioral neurology at the Veterans Affairs Boston Healthcare System, who has patients in both the intermediate and advanced trials. “I think most people in the Alzheimer’s field are aware of this, but also think it’s unlikely to work, so they’re not watching it closely.”
The company hasn’t published its full data from the study yet, making it hard for neuroscientists to vet. Vaughan said he plans to submit a paper to a medical journal this week, and noted the final efficacy figures are a bit lower than previously reported: 76 and 77 percent slowing of cognitive and functional decline, respectively.
Should those numbers pan out in a larger study, it would suggest that the device slows the disease far more than Leqembi, the recently approved infusion therapy for Alzheimer’s made by Biogen and Eisai. Leqembi slowed cognitive decline by 27 percent over 18 months — albeit on a different scale and with different criteria for being included in the trial.
Tsai said that understanding exactly what is happening in the brain during gamma wave therapy is now “the major research effort” in her lab. Over the past few years, her team has found that the treatment enhances blood circulation in the brain, replenishes the density of connections between brain cells, and restores the ability of helper cells called microglia to clean up debris that accumulates in the aging brain, including amyloid plaques and another problematic protein called tau.
Other academic labs have turned their attention to gamma waves, too, with mixed results. A study published earlier this month by György Buzsáki, a neuroscientist at New York University, was unable to replicate the incredible results that Tsai and Boyden reported in 2016.
Excitement for the approach runs the risk of outpacing the science. Some companies have begun selling devices designed to trigger gamma waves without first proving that the devices are effective.
Solomon said that no study thus far, including Cognito’s early ones, is enough to convince experts that gamma wave is “ready for primetime.” But he thinks the company’s new clinical trial will help provide those answers within the next two years. Many of his patients have been interested in joining, and he thinks there’s little to lose in giving it a try.
“The risks are never zero, but it is as close zero as you can get,” Solomon said. “And we still have some people from that [first] study who don’t want to give the kits back. And I’m not going to go and take it away from them. They just think that this has helped.”