Today, nearly six million people in the United States suffer from severe memory loss and other impairments caused by Alzheimer’s disease. By some estimates, another forty-six million or more are on their way to developing Alzheimer’s without even knowing it, and scores of long and costly clinical trials have failed. Unless scientists can figure out how to break the impasse against this dreaded disease, it could cost more than $2 trillion globally in the next decade. But despite these grim facts, many researchers argue that there are reasons for optimism, not least of which is a willingness to look outside the spotlight and try fundamentally different tactics.
One such researcher is Michela Gallagher who has been studying memory since the mid 1970s. When Gallagher first started out, Alzheimer’s disease was not even part of her thinking. Today, she is the driving force behind a phase three clinical trial that seeks to address a rarely discussed phenomenon of Alzheimer’s—hyperactivity in the hippocampus. “The thing that’s unusual about me,” says Gallagher, “is that I do a lot of really basic neuroscience. One of my areas was studying aging as an experiment of nature to understand memory systems better. It wasn’t because I wanted to understand Alzheimer’s disease. It was just—I’m interested in memory.”
For many years, the reigning theory was that this hyperactivity was compensatory, making up for the loss of healthy neurons in aging brains, especially those with Alzheimer’s. But Gallagher didn’t think so. Somewhat to her surprise, she found that this heightened electrical activity began before neurons were dying. That aside, Gallagher didn’t think extra activity would help the hippocampus make better memories.
“It seems like it would, but if you understand how that system worked, you would say that’s a big problem.” Instead of turning up the volume on faltering communication, this activity acts like static in the background, interfering with the hippocampus’s exquisitely tuned circuitry. Proving her point, Gallagher found that the higher the activity, the harder it was for rodents to navigate through a maze or find the escape platform in a tank of water. So she decided to see if she could help by giving them a very low dose of an anti-seizure drug that tamps down runaway activity, and it worked.
Gallagher’s team then analyzed human brain scans to look for hyperactivity in the hippocampus. She discovered that older people, especially those with amnestic mild cognitive impairment, had this same signature. So do people who carry the APOE4 gene variant, the greatest known genetic risk factor for the disease. “So, then I went into humans and said, okay, I’ll just do the experiment. I’ll see if this drug treatment will bring that overactivity down as we monitor it with brain imaging. If it’s compensatory, their memory will get worse. If it’s the same as in the rats, their memory will improve. And it turned out they were the same as rats.”
After several smaller successful clinical trials, Gallagher now has the evidence to justify a Phase 3 trial—the final step on the road to a new treatment. Although her proposed strategy is outside the mainstream, Gallagher’s results were enough to secure multiple grants and launch a company called AgeneBio. In January 2019, AgeneBio began enrolling patients in a trial slated to run at twenty-six sites across North America. The patients are between the ages of fifty-five and eighty-five and will take either a placebo or a very small, specially formulated dose of the anti-seizure drug levetiracetam, called AGB101, for a year and a half and track whether the drug slows the progression of memory loss. Patients will also undergo PET imaging for tau and amyloid. If the drug works, Alzheimer’s patients will someday have access to a once-a-day pill instead of the expensive infusions that would be required for proposed anti-amyloid therapies, like Biogen’s aducanumab.
But Gallagher doesn’t expect AGB101 to be a cure for Alzheimer’s. The goal is to stave off the progression of the disease. Even buying as little as one to two years could result in 10 to 20 percent fewer people with full-blown Alzheimer’s. She has her sights set on an even bigger prize. “The idea here is that if our therapeutic works in MCI—and that’s the study we can afford to do, barely—I think it will work earlier and truly be a preventative strategy.”
The seeds of Li-Huei Tsai’s interest in Alzheimer’s were planted when she was three, on the day her grandmother forgot where they lived. On their way home from the market, the two took shelter from the rain at a bus stop. But when the rain ended and Tsai said it was time to go home, the old woman didn’t know where home was. Tsai can still see the look on her grandmothers’s face.
Today Tsai is the director of the Picower Institute for Learning and Memory at MIT in Cambridge. Rows of Veuve Clicquot champagne bottles, the souvenirs of decades of scientific achievements, line the shelves above her desk. Less conspicuous is a device you could mistake for a whiteboard, which Tsai turns on and sits in front of for as long as an hour a day, day in and day out. It emits flickering white light and a strange buzzing tone called pink noise. Both the light and the sound oscillate forty times a second in what’s called a gamma wave. “I love to expose myself to gamma tone and gamma light,” Tsai says.
The brain has a handful of innate brain rhythms—delta, theta, alpha, beta, and gamma—which range in frequency from about 1 to 150 times a second; scientists believe these waves make it possible for billions of neurons to coordinate the information they share. Imagine sitting by a lake watching four people in four rowboats, all rising and falling together on the waves. The people aren’t secretly communicating with each other, nor are they physically connected. Instead, the same waves rock the boats. All four get the same information, so even though they’re separated in space, they act as one.
Gamma waves orchestrate the activity of neurons throughout the brain. Stronger gamma, waves with higher peaks and lower troughs, are associated with paying attention, better working memory, sensory processing, and spatial navigation. Tsai is interested in gamma because it’s weaker in people with Alzheimer’s. What’s more, gamma is weaker even before amyloid beta plaques—the sticky clumps of toxic proteins that are a hallmark of the disease—begin to accumulate. The possibility that weak gamma could be among the earlier things to go wrong in Alzheimer’s patients is just one of many lines of evidence that lead her to believe that the hour each day she spends in front of her device is time well spent.
So, what sets up these waves in the first place? Neuroscientists will tell you that they don’t completely understand it, like so much else about the brain. But it seems to work in a yin-yang kind of way. The firing rates of cells create brain waves, and brain waves, in turn, orchestrate cells’ firing rates. One type of neuron, less plentiful but more diverse than the rest, is in charge of these rates. They’re called inhibitory neurons, and without them, the brain would be chaotic. Most neurons are excitatory; they receive messages from other neurons, and if that message is loud enough, they’ll fire and pass it on. Like bouncers at a bar, inhibitory neurons keep the excitatory neurons under control. As a general rule, when they fire, they turn those excitatory neurons off.
Inhibitory neurons come in many shapes and sizes throughout the brain. One is called a basket cell. Its axon splits into many filaments and wraps around an excitatory neuron’s cell body, the point where the axon exerts maximum influence. A single basket cell can synchronize and control the output of hundreds or even thousands of excitatory neurons, switching them on and off with precise timing, setting up a rhythmic tug-of-war that creates the waves. When basket cells are activated and entrained at forty times a second—in theory, by any input that oscillates at 40 hertz, such as light, noise, smell, or even touch—the peaks and troughs of the gamma wave are strengthened.
Tsai’s lab began to explore the effects of entrainment using light. They inserted fiberoptic wires into the brains of mice engineered to produce extra amyloid beta, and shone 40-hertz light down the wires directly into the hippocampus, where it activated only the inhibitory neurons. After one hour of treatment, scores of genes turned on. Microglia, the brain’s immune cells, changed shape to prepare for their house-cleaning role and nearly doubled in number. Briefly, the levels of amyloid beta decreased. Tsai was floored. “I said, ‘Oh my God, you’ve got to repeat it to see if this is real. This is too surprising.’” She also knew that even if her team could replicate the experiment, the results would only be useful for people if she could find a way to strengthen gamma without inserting wires into their brains.
In follow-up experiments, mice unencumbered by wires spent an hour a day hanging out in darkened rooms in small boxes lit by flashing LED spotlights. Light doesn’t penetrate all the way to the hippocampus, but it can entrain brain waves in the visual cortex, where sight is processed. Treating the mice an hour a day for seven days reduced not just free-floating amyloid beta, but also amyloid plaques and toxic tau. But this was only in the visual cortex. Tsai needed to find out if the beneficial effects of flickering light could reach ground zero, the hippocampus. When her team upped the hour-a-day exposure times from one week to as much as six, gamma strengthened in the hippocampus, fewer neurons died, and the mice were better at remembering where to find the hidden escape platform in a water tank.
Tsai’s team tried using 40-hertz pink noise instead of light and was able to achieve similar effects in only one week. The diameter of blood vessels also expanded, which may, in turn, help clear out amyloid beta and tau. And when mice were exposed to light and sound at the same time, there were fewer amyloid beta plaques throughout the brain, and microglia clustered around the ones that remained. Tsai’s team is trying to work out why this non-invasive treatment has such profound effects, but the potential for Alzheimer’s patients seems too great to wait for the answers.
In 2016, Tsai and a collaborator at MIT named Ed Boyden founded Cognito Therapeutics to explore whether gamma entrainment using light and sound works in people. Ninety participants are being tested at multiple locations in three trials using Cognito’s device. One trial was slated to report results in October 2020, another in 2021, and the third in 2022. At MIT, Tsai is running her own small clinical trial to assess the effect of daily treatment for up to nine months, with results expected to be reported in 2025. “My dream is that perhaps one day we can try to create a ‘gamma society,’” she testified before Congress in 2017. “We can try to change our lighting system(s) at home, or on the streets, the refresh rate of computer monitors or TV, or people can get exposure to the gamma flicker more readily, to create a healthy society.”
Her optimism is tempered with humility. “On the surface, we seem to know a lot about Alzheimer’s disease, but when it comes to intervention, it has been a humbling process,” Tsai told an audience of neuroscientists two years later. “We’ve been burned hundreds of times.” Although neuroscientists agree that the function of brain waves remains enigmatic, manipulating this activity holds promise in other brain disorders, including Parkinson’s, epilepsy, and mental illness.
Saul Villeda looks lovingly at his two mice, tracking their movements around the cage. He knows you should never name them because you get too emotionally attached. He made that mistake once. One mouse is old, the other is young, and they’re surgically connected along the length of their abdomens, moving as if they were born that way. Villeda is an assistant professor at the University of California San Francisco (UCSF). He grew up poor in East Los Angeles, and he’s the first in his family to go to college. He thought he wanted to be a mechanic, but a professor noticed that Villeda looked at things from a different angle and encouraged him to think again.
Rather than tackling Alzheimer’s head-on, Villeda looked at this disease of aging and asked, “Can I make something young again?” That’s where his stitched-together mice—whose blood flows freely from one to the other—come into the picture. These lab mice are inbred, so there’s no tissue rejection, but they’re otherwise natural. Typically, the young mouse is about three months, and the older one is between a year-and-a-half and two years old. That’s like attaching a person in their mid twenties to someone in their late sixties or early seventies.
Young mice run around a lot, their fur is glossy and thick, and they have an easier time remembering where to find hidden a platform in a large tank of water. Old mice are forgetful. They have dull, patchy fur. They’re slow and frail. Before, during, and after the operation, the mice are treated with as much care as human patients. The surgeons, one for each mouse, wear hairnets, booties, and smocks to keep conditions sterile. The mice are anesthetized before the surgeons cut through the skin and the membrane surrounding the abdominal cavity, then suture the two cavities together to create one big sac. They connect the leg joints where the two mice meet so the animals won’t pull at the scar, then sew them up.
Within three weeks, the mice have learned to walk as one. Within ten days, the stress hormones caused by surgery go down, just as they would in a person. Within two weeks, the same blood is flowing between them, and the transformation begins. After five weeks together, Villeda’s old mice look healthier, and their memory improves. “We never get an old animal back to a full young animal,” says Villeda. “It’s probably bringing someone in their seventies back to around forty. But not twenty.” Unfortunately, the effects go both ways, and the young mice get the short end of the stick, looking and acting like fifty-year-olds. Barbaric though parabiosis sounds, it’s an efficient way to test the concept: infusing an old mouse with enough young blood plasma to make a difference would require sacrificing many more animals.
In 2014, when Villeda was a grad student at Stanford, Nature Medicine published his proof-of-concept results showing the rejuvenating power of young blood. Other scientists were also finding blood factors that reverse aging throughout the body, including the brain. “There’s an incredible amount of plasticity left in the old body, including in places like the hippocampus,” says Villeda. “And the best part about it is that you don’t have to drill holes to get into the brain. It’s screaming therapeutic potential.”
The results were so appealing that it wasn’t long before a start-up California company named Ambrosia began charging people thirty-five years or older eight thousand dollars to be transfused with young blood plasma. After the FDA issued a warning that the treatment hadn’t gone through rigorous testing to ensure that it was either safe or effective, the company shut down.
Essential safety concerns aside, there’s not enough young blood in the world to treat every Alzheimer’s patient today. Villeda’s parabiosis experiments are just screening tools to help hone in on which of the hundreds of factors—proteins, antibodies, clotting factors, electrolytes, or hormones—circulating in blood plasma either turn back the clock or speed it up. Because exercise has such proven benefits on aging, Villeda decided to search there. After giving his aged mice continuous access to treadmills for six weeks, he sorted their blood plasma to see which factors went up. There were thirty—too many to test. So he winnowed it down to those involved in metabolism and, from there, zeroed in on an obscure enzyme that the liver pumps out after exercise.
Why an obscure enzyme? “I’ve been pursuing factors that we don’t know very much about,” Villeda says, “because, in my mind, it’s probably something we’ve overlooked.” To test whether his hunch about this enzyme was correct, Villeda created mice that pump out much more of it than usual. After three weeks, these genetically engineered mice had more neurogenesis and performed better on memory tests. Villeda partnered with Joel Kramer and Kaitlin Casaletto at the MAC, who found that this enzyme is also higher in older people after they exercise. But not everyone can exercise. If this liver enzyme could be distilled into a pill, it could help treat people too frail to get on the treadmill. Other labs such as Stanford, Columbia, and Harvard are also investigating the rejuvenating effects of young blood. Several clinical trials are already underway, including one at multiple locations across Spain and the United States.
Villeda, Sahay, Tanzi, Gallagher, and Tsai are just a handful among many researchers who want to intervene in the process of aging to slow down or prevent Alzheimer’s. And while these approaches may seem vastly different, Villeda says that “there are enough commonalities between all this research that there’s some fundamental truth there that we can tap into.” Researchers are working on transplanting healthy inhibitory neurons into an aging mouse hippocampus, boosting the brain’s ability to clear out plaques and tangles, or rejuvenating the neurons’ metabolism to counteract the effects of aging. Like other chronic diseases—mental illness, HIV/AIDS, high blood pressure—multiple treatments may be most effective.
“I think there’s no silver bullet,” says Gallagher. “Ultimately, when we have relegated Alzheimer’s pretty much to the history books, it’s going to look more like HIV/AIDS—not the biology of it, but there’s going to be some combination of therapeutics.” Curing Alzheimer’s will be hard, but no one in the field is giving up, despite past failures and all the reasons why Alzheimer’s is a formidable disease. “Being a researcher is inherently an optimistic choice because it assumes that there’s light at the end of some tunnel,” says Howie Rosen at the Memory and Aging Center at UCSF. “And that if you keep walking, you’ll get there.” The stakes are too high not to keep on walking.
This essay was adapted from The Memory Thief and the Secrets Behind How We Remember: A Medical Mystery by Lauren Aguirre (Pegasus Books).
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