Peg Gleason, who is 83 and lives in San Francisco, was the first to sign up for the initial human trial of an MIT-backed experimental treatment for Alzheimer’s disease last January.
The trial had a slightly eccentric setting at the warehouse offices of TheraNova, a San Francisco-based medical-device developer. Seven days a week for seven months, until the study ended, Peg and her husband Ed, 85, were dropped off by Uber at a side door and taken to a small room inside an old metal vault.
The experimenters were “all very good and smart people, and they were all 32-and-a-half-years old,” Ed, a retired product manager for AT&T, joked.
“They put very large sunglasses on Peg with the lenses blacked out,” he said in a phone interview, in which Peg also participated. “[They] taped very small LED lights to them, so that when you put them on, all you saw were the four little lights on each lens. And they would be calibrated to flicker at 40 hertz.”
Along with the glasses, Peg was fitted with earphones that played a tone at 40 hertz, and pads on each hand that vibrated at that frequency. The treatment lasted an hour a day, with another 15 minutes for post-trial cognitive testing, and then the Gleasons were driven home.
The San Francisco experiment began last January, a month after Nature published an MIT study reporting that exposure to LED lights flickering at 40 hertz (40 cycles per second) was linked to a sharp reduction in beta-amyloid plaques—clumps of abnormal proteins — in the visual cortex of mice bred to develop an Alzheimer’s-like disease.
Neurons in the brain sometimes fire in synchrony, producing brain waves. Brain waves around 40 hertz, in the so-called gamma band — a frequency associated with higher-order cognitive functions, such as working memory and spatial navigation—have long been known to be impaired in Alzheimer’s disease and some other brain-based disorders.
Disrupted gamma activity is also characteristic ofmice bred to develop Alzheimer’s disease, MIT professor of neuroscience Li-Huei Tsai, the lead author of the Nature paper, explained in a presentation to a congressional panel last July.
But after experimental mice spent just one hour daily for a week in a box fitted with LED lights flickering at 40 hertz, she said, their gamma brain waves rebounded, and amyloid plaques were reduced by half.
The mice were also able to learn again. “They can remember an object in an environment, they can remember a place and they can navigate better,” Tsai said.
What happened? Tsai said that the 40-hertz flicker “entrained” the mice’s brain waves to follow along, syncing in the gamma frequency. Such syncing was first demonstrated in cats in the 1990s, she said, pointing at a GIF of a cat staring at a blinking light.
It’s not clear how, Tsai went on, but restoring the mice’s gamma brain waves also revived their microglia, the brain immune cells that clear toxic substances like amyloid and that are “on strike” in Alzheimer’s disease.
“These janitor cells, the microglia, become active again,” Tsai said. “They become larger in size, their branches become more complex, and there are just more of them. But more importantly, they are very busy gobbling up this amyloid.”
Tsai said that neurofibrillary tangles, another marker of Alzheimer’s, “disappeared” in the experimental mice. Blood vessels in their brains also changed, with the lumens — the interior channels — dilating twofold.
“But it doesn’t stop there,” she said. “In the Alzheimer’s brain, a large number of neurons die, and the brain becomes smaller.” Six to eight weeks of daily exposure to 40-hertz light, however, “protected the brain cells from dying, it prevented the brain from shrinking. And the synaptic connections, the density, is restored.”
Most spectacular, and what made Tsai “speechless,” was that the effects spread beyond the visual cortex to the rest of the brain, “including the hippocampus, the memory center, and the prefrontal cortex, the part of the brain known to be important for making decisions and performing executive functions.”
When the lights were stopped, however, even for only 12 hours, the amyloid plaques rebounded. And the flickering had to be at 40 hertz; other frequencies or random flickering had no effect.
Tsai and her colleagues checked and rechecked their findings. “We were excited, but we were also very anxious,” she said. “It was such an unbelievable and unexpected result. We just had this anxiety to repeat it as many different times as possible, to get as many different people to repeat it.”
“In my wildest dreams, I never thought I would come upon this kind of observations, this profound, this sort of hard-to-believe,” Tsai, who directs MIT’s Picower Institute for Learning and Memory, said on an Amazing Things podcast.
Last fall, soon before their Nature paper was published, Tsai and her lead co-author, MIT professor Edward S. Boyden, founded a startup, Cognito Therapeutics. Backed by MIT and with venture capital funding, the firm aims to develop “device-based” therapies for Alzheimer’s and other neurodegenerative diseases.
Cognito engaged TheraNova in San Francisco for the human feasibility study last January. Ed and Peg Gleason learned of it from a flyer passed along by a friend at the University of California Medical Center.
They had little to lose; there is no cure for Alzheimer’s, the most common form of dementia. It does not kill quickly, but over months or years as the brain progressively fails and victims lose all ability to communicate or care for themselves. Alzheimer’s is now the third leading cause of death among older Americans.
Peg was diagnosed in 2011, when an MRI during a routine physical found shrinkage in her frontal lobe.
“When she explained that it was Alzheimer’s, I looked at her and said, ‘No, no, that’s not me, I don’t have anything wrong with me,” Peg said. She ran out of the doctor’s office, crying. In the six years since, her short-term memory has declined. She rarely remembers events from earlier in the day, even something memorable, like a visit from one of their six children.
But within days of beginning the trial at TheraNova, Peg’s memory improved. She began to remember events from the day before, not always, but far more often. Their children remarked on it.
Peg also seemed mildly euphoric after the sessions, telling Ed she felt good. “It would last for two or three hours after every treatment,” Ed said.
The researchers seemed sanguine about the results as well. Two staff members told Ed that everyone in the pilot study—five people were enrolled in all — was showing improvement.
About a month into the trial, however, the experimenters announced a hiatus. “They said, ‘We’re going to stop the study and evaluate,’ Ed said. “I don’t know what they were thinking. I would not like to think that we were guinea pigs, and that they wanted to see if there was, you know, a recession, a bad effect.”
But within a few days, Peg declined. "I told them," Ed said, "the plaque is coming back; it’s like the fog coming in from the ocean."
The researchers were noncommittal. “They would say, ‘The time is up for the study, we’re going to review where we are.’”
After eight days, Ed got a call that the trial was resuming, and a car would pick them up again the next day. The daily sessions continued after that without a break, except for a few weekend days, until mid-August.
Then, with a week and a half’s notice, the study ended. The researchers said the trials were being moved to Boston, where Cognito is based.
Immediately, Peg drooped again. By late September, five weeks after the study ended, there was a significant decline in her short-term memory. Ed said, "her anxiety and sundowning became more pronounced, and there’s more confusion.”
For the first time, she failed to recognize Ed. A few times, she thought Ed was her father. She also wandered off twice, something that had not happened before.
Peg's grandmother died of Alzheimer’s, as did her older sister two years ago.
“The one thing I want to know," Peg said, "is how much I’m going to expect. I don’t want to hurt him or the kids.”
As the trial came to a close, Ed began asking the researchers to allow Peg to continue her daily treatments, or for help putting together a device to use at home. He’d been told they were assembled with off-the shelf components and powered with 9-volt batteries. The 40-hertz lights should be simple enough to replicate by someone with electrical engineering skills; several YouTube accounts had already posted schematics.
But Ed didn’t know anyone with those skills other than the TheraNova engineers. And verifying that a light is truly flickering at 40 hertz requires an oscilloscope, which costs thousands. Still, he ordered a $40 string of 40-hertz LED lights from a new online business, gammalighttherapy.com, that was founded in mid-August (its website refers to the MIT research), and a "gamma bulb" from another.
He also searched out 40-hertz sound on YouTube videos posted by New Age and brain hacking enthusiasts, who have long used the tones in meditation; they point to studies at the University of Wisconsin that found strong gamma brain-wave activity in meditating Tibetan Buddhist monks.
He and Peg began listening to the sound together on earphones for an hour every day. It seemed to help, but in the evenings Peg’s confusion returned. Ed continued to call and email the researchers at Cognito and TheraNova, asking for their help and growing angry when they did not respond.
On September 27, 12 days after Ed’s last email, Cognito general manager and president Zach Malchano wrote back. He said he was very sorry to hear of Peg's decline, but that no further trials were planned for San Francisco, and the company could not provide access to an unapproved medical device.
Malchano declined to be interviewed, but emailed a statement that said Cognito would not allow access to investigational devices, even under a compassionate-use program, because of the early stage of the research and Cognito’s “size and resources." Malchano also wrote: "Many of us at Cognito have personal connections to the disease and are working as quickly and as hard as we can to study the effectiveness of this technology in trials necessary to understand the potential effectiveness and safety of this approach."
The Food and Drug Administration approves almost every compassionate use request for seriously ill patients who lack therapeutic alternatives — but only if the medical developer agrees.
Ed says it is unethical of the researchers to abandon Peg to her disease.
“We are guinea pigs; we signed the paper,” Ed said, “But if you know the plaque is coming back in the mice, then you can assume the plaque is coming back in the people, and you have to address that. That’s your moral responsibility.”
A friend puts it more starkly: “It’s like testing to see whether a life raft works, and throwing the person back in the water.”
There’s something reminiscent of "Flowers for Algernon" in the Gleasons’ experience: eager scientists, a seeming improvement and then rapid, hopeless regression. Ed contends that the MIT scientists, whose research was partly funded by federal grants, are also wrong to seek ownership of technology and concepts that aren’t particularly novel.
“They can’t patent 40 hertz any more than General Motors can patent 40 mph,” he said.
Other researchers, in fact, have investigated gamma brain-wave-inducing devices in human subjects. A 2016 University of Toronto study reported improved cognition in Alzheimer’s patients after six sessions in vibroacoustic therapeutic chairs with built-in speakers set at 40 hertz.
Devices to entrain brain waves via audiovisual stimulation have also been used by psychotherapists and sold to the public for a decade.
Psychologist Ruth Olmstead, who authored a 2005 Journal of Neurotherapy paper about audiovisual entrainment for learning disabilities, sells a “Synaptic Stimulus Trainer” with a headset that looks like the device used in the San Francisco study. Like other such devices that claim to increase creativity, treat depression and sleep disorders, or help children with learning disorders, it is marketed with a disclaimer that it is only for “recreational” purposes.
For her part, Li-Huei Tsai says she doubts exposure to 40-hertz LED lights could do harm, but that DIY attempts at brain-wave entrainment at some intensities could potentially be dangerous.
Results from the “extensive, rigorous, really well-controlled, blinded” studies that are necessary, Tsai said in a phone interview, might be available in three or four years. She declined to answer questions about the TheraNova study, or the 12-patient study now underway in Boston.
In her summer presentation to Congress and on the podcast, Tsai was less guarded, saying she was hopeful that 40-hertz research would yield noninvasive treatments that could be “life-changing for millions.”
“My dream is that perhaps one day we can try to create a ‘gamma society,’” Tsai said. “We can try to change our lighting system(s) at home, or on the streets, the refresh rate of computer monitors or TV, so people can get exposure to the gamma flicker more readily, to create a healthy society.”
Peg Gleason will be long past helping before then; probably long before clinical trials are done. As of mid-November, her confusion and sundowning had continued to grow worse. She was mistaking Ed for her father again. She didn’t want to listen to the sound or look at the lights, and he’d given up searching for another device. He hoped to be able to keep taking care of her at home. On December 7, he emailed:
"Peg has declined. When she entered the study she was seen as stage three of seven, she stayed in 3 for the whole trial until August, At the end of trials she immediately regressed to 4 in my opinion. When she fell and got an infection she went to 5 Now, the last week she has entered 6, Our support group leader said the decline can be quick, We will see. I'm determined to keep her at home as even the best and most expensive places are a sad end. I promised myself and Peg that I would accompany her at home to the end with the help of my children and grandchildren."