Photograph by Hannah Whitaker for TIME

Alzheimer’s from a New Angle

A radical new approach to treating the fearful disease is showing promise
Hannah Whitaker for TIME A radical new approach to treating the fearful disease is showing promise

A radical new approach to treating the fearful disease is showing promise

Dr. Frank Longo isn’t the kind of guy who chokes up easily. The pre-eminent neurologist is better known for his professional stoicism and scholarly approach to the devastation he sees weekly in his Alzheimer’s patients–the people who come into his office at the Stanford University School of Medicine, their memory just a little bit worse than the last time he saw them. But today, even though he’s trying to keep it together, his throat tightens.

He’s in a small exam room outside Kansas City, Kans., watching a young man do something people do every day. He’s swallowing a pill with a big gulp of water. But it’s not just any pill–it’s a new drug that Longo hopes will prove to be an effective treatment for Alzheimer’s–and when the man swallows, tears pool in the deep furrows around Longo’s eyes.

As chairman of the department of neurology and neurological sciences at Stanford, Longo knows how destructive Alzheimer’s can be. He specializes in memory disorders and regularly sees patients whose brains are slowly scrambling. In recent years he’s grown frustrated. Alzheimer’s was first discovered in 1906, which means doctors have had a century to peel away the disease’s molecular layers and search for a cure. But despite their best efforts, they still have no real treatments. Since 2000, more than 200 Alzheimer’s drugs have been tested, and none proves to be a silver bullet. Only a handful of drugs can, in the best-case–but rare–scenario, relieve some of the worst problems of memory loss and confusion.

“My biggest frustration is that we’ve cured Alzheimer’s in mice many times. Why can’t we move that success to people?” Longo says. (He’s referring to numerous promising compounds that have eliminated the amyloid plaques associated with Alzheimer’s in animals.) If the ongoing human trials continue to progress the way he hopes, Longo’s drug, called LM11A-31, could be a critical part of finally making that happen. But that’s still a big if.

To further develop the drug for patients, Longo created a company, PharmatrophiX, which conducted the first phase of clinical trials required for all pharmaceuticals; the drug was deemed safe and caused minimal negative side effects. Now, it’s in phase II, when the drug will be tested in people with the disease, to see if it ameliorates their symptoms. If the trial goes the way Longo and other leading Alzheimer’s experts expect, LM11A-31 will then be on its way to being approved by the Food and Drug Administration.

The stakes couldn’t be higher–not just for Longo but also for the world’s aging population. In the U.S., one-third of Americans over 85 are already affected by Alzheimer’s. Globally, nearly 50 million people are living with dementia, most of which is caused by Alzheimer’s, and absent effective drugs or other interventions, that number is expected to double every 20 years. With no treatments, caring for them falls to loved ones and assisted-living facilities. The cost of that care is skyrocketing; in three years, the global annual burden could reach over $1 trillion.

Longo’s drug is noteworthy because of the promise it showed in those mouse studies and because it’s been shown to be safe in humans. But what really sets it apart is that it attacks Alzheimer’s in an altogether different way than the drugs that preceded it.

“The field is taking a step back and re-examining where we are with regard to what we know, what we don’t know and what might be some of the best avenues going forward to look for treatments,” says Dr. Ronald Petersen, director of the Mayo Clinic Alzheimer’s Disease Research Center and the Mayo Clinic Study of Aging, who is not involved in the LM11A-31 research.

For decades, scientists have pursued a cure with a nearly single-minded focus on how to treat the disease: by trying to get rid of the hallmark feature of Alzheimer’s, which is sticky, insidious protein plaques of amyloid that they have fought so well in mice. If they could get rid of that in humans too, the thinking went, they could get rid of the disease–or at least lessen its severity. But LM11A-31 doesn’t directly attack amyloid at all.

“We’re agnostic about what is actually causing Alzheimer’s,” Longo says, referring to those protein plaques. “Most people are working at the edges of the problem, but we’re going right after the core of it.” LM11A-31 isn’t designed to chase after every last clump of amyloid and wipe it away. The core, in this case, is simply to keep brain cells strong, protected against neurological onslaughts, whether they’re the effects of amyloid or other factors involved in Alzheimer’s. It’s a much less orthodox approach, but–as Longo’s emotion suggests–if it works, it could be a game changer.

Aging, of course, is inevitable, but aging well is not. No one would argue that finding ways to help people remain healthy, functional and productive for as long as they can isn’t a good idea. That’s why, as life spans continue to inch upward, more health experts are focusing not just on extending the number of our years but on making sure they are of the highest quality possible. Keeping the brain robust and free of damaging conditions like Alzheimer’s is an essential part of that health span. Which is why brain experts are flipping their perspective and studying not just how our physical and mental abilities falter as we age but also how they keep going year after year.

“The answer to extending healthy life spans lies not in how we break down at age 70 but in how we keep functioning at age 50,” says Brian Kennedy, president and CEO of the Buck Institute for Research on Aging. Understanding how to do that could not just protect the brain from Alzheimer’s but also serve as a longevity insurance policy to keep it humming along at close to full capacity for as long as possible.

Under a microscope in his lab at Stanford, Longo shows off before-and-after slides of some brain neurons from mice. On the before slide, the normally orderly and uniform cells are in disarray. They’re dying, slowly being choked off from their supply of nutrients by amyloid plaques that start to accumulate like molecular garbage in certain corners of the Alzheimer’s-afflicted brain. In the after slide, the cells look normal. The difference, Longo says, is LM11A-31.

For brain cells, their molecular connections to other neurons are their lifeline–it’s like their version of Twitter, as they constantly ping other neurons with status updates. But when the cells are assaulted by something like amyloid, these communications are threatened. And in response, those cells tend to make a quick exit–toward death.

To treat the degradation, scientists logically focused first on finding ways to soak up the excess amyloid in the brain, hopefully before the protein can form its tacky plaques and destroy neurons. They developed, among other drugs, antibodies to find and bind to amyloid and break it down. But these compounds, though they worked in animals, failed to make much difference in memory and cognitive function in people.

That prompted experts to consider that maybe the problem wasn’t the drugs but when the drugs were given. Perhaps there was too much amyloid, and too much damage in people with advanced disease, for the drugs to have any measurable effect. For that reason, some companies aren’t giving up on their failed drugs and have begun testing them, with promising results, among people with early-stage disease, when there’s less damage from amyloid. Genentech, for its part, is testing its anti-amyloid drug in Colombian families who have a high genetic risk of getting Alzheimer’s; the company hopes that giving the drug to asymptomatic people highly likely to get the disease can slow their cognitive decline.

But that requires knowing when the amyloid makes its first appearance. And there’s another problem: about 30% of people over 70 have amyloid in their brains but no signs of dementia. In other words, everyone with Alzheimer’s has amyloid, but not everyone with amyloid has developed Alzheimer’s. Which people need help from anti-amyloid drugs, and which people don’t? Which ones can wait before taking the drugs? Until recently, the only way to definitively diagnose Alzheimer’s was in a postmortem, when the brain could be studied for signs of the amyloid plaques. Now, thanks to new imaging agents that light up amyloid on scans, researchers can track the earliest appearance of these proteins and see if they grow, which could signal Alzheimer’s.

There’s similar momentum building around possible treatments against another major Alzheimer’s protein, tau. If amyloid is the locomotive of the disease, driving the damage to neurons, then tau is the caboose, generally appearing in the late stages, when memory, organized thinking and language start to fail. By the time tau breaks down to form tangles, the brain has already started to degenerate, meaning it’s shrinking in size as neurons are dying and certain parts, specifically the hippocampus, the hub for memory, start to atrophy. That’s why memory problems and cognitive functions start to go.

“We think that tau may incite the whole process of neurodegeneration,” says Dr. William Jagust, a professor of public health and neuroscience at the University of California, Berkeley. “That’s important if you think of Alzheimer’s as moving through standardized group stages. The first stage is [depositing] of amyloid. In the second stage, something probably happens with tau. Somewhere in there we begin to see neurodegeneration.”

To interrupt this process, you need good drugs that can intervene at any or all of the stages. Even though doctors can now see amyloid deposits in the brain, for example, they don’t have anything that can remove the plaques. Same goes for anti-tau drugs. “If we have a drug for treating amyloid, then that obviously changes the whole story,” says Jagust. But we don’t–at least not yet.

That’s where LM11A-31, or C31, as Longo’s team calls it, may come in. Together with the anti-amyloid and anti-tau therapies, it could be a potent counterpunch to any neurological problems, from memory loss to confusion and loss of language.

Longo has a diagram of 14 signals passed among brain nerves that are triggered by amyloid and can ultimately lead neurons to deteriorate. So far, he’s found that C31 can halt at least 10 of those. “We lucked out in a way,” he says, since just targeting the receptor P75 that sits on brain nerve cells, as his drug does, can interrupt a cascade of unhealthy signals that instruct brain nerves to falter.

That might allow doctors to prevent some of the damage caused by amyloid before it occurs. “Growth factors might come into play to regenerate, restore and preserve connections between nerves,” says Petersen. Theoretically, he says, if someone at high risk of developing Alzheimer’s shows signs of amyloid on their brain scans, “you could squirt them with [nerve-growth factors] to try to prevent or ameliorate the things that are doing harm to nerve cells. So can we prevent Alzheimer’s with nerve-growth factors? That’s not an unreasonable hypothesis.”

C31 even shows signs that it might help people whose brains are already damaged by amyloid. “The general assumption was that the damage to brain neurons was irreversible,” says Longo, “and that it would be nearly impossible to get them back. What our studies show is that in mice, there is a significant amount of damage that is reversible. That’s really unusual,” he says.

The impact of that feat, if it’s repeated in humans, would be huge. “If approved, these could be the first drugs that will change the course of the disease” rather than just treat its symptoms, says James Hendrix, director of global science initiatives at the Alzheimer’s Association. But the reality is that it’s not clear yet whether the changes seen from drugs like C31 restored any lost memory. Brain experts are eagerly awaiting Longo’s next series of studies for the answer to that question. So far, not everyone is convinced that it’s even possible to rescue already compromised nerve cells. “To bring back neurons that have been destroyed by plaques and tangles–to me that still seems almost like science fiction,” says Hendrix. “I have a hard time getting to that point.”

Still, there’s no denying the potential of compounds like C31 and the need to think about new ways to attack the disease. Researchers at the Rush Alzheimer’s Disease Center recently reported intriguing evidence that people with higher levels of an important nerve-growth factor called BDNF tended to keep more of their cognitive functions even when amyloid built up. In fact, people who had more BDNF activity saw a 50% slower rate of cognitive decline over the study’s six years than those with lower activity. So far, researchers think that having higher levels of factors like BDNF might give people cognitive reserve–the ability to counteract any damage that’s occurring and minimize its effects. (There is no drug that boosts BDNF levels, however–at least not yet.)

Longo’s C31 is the first drug to be tested in people that capitalizes on this idea of topping off levels of nerve-growth factors, and it’s gaining more supporters. “The old approach was to try to modify what went wrong in Alzheimer’s,” which in this case is the buildup of amyloid, says Dr. Aron Buchman, a professor of neurological sciences at Rush who was part of the BDNF study. “This new approach says, Let’s find factors, proteins or behaviors that may protect people against the ravages of the pathologies that are likely accumulating in nearly all people as we get older.”

Some experts are convinced that if people live long enough, some form of dementia, most likely Alzheimer’s, is inevitable. It’s just a matter of time. But figuring out which people can benefit from which types of treatments–and when–is still an open question. The hypothesis that dementia is inevitable is unpalatable to doctors like Longo. But it’s a reality that even the government is starting to appreciate. In 2011, Congress created a National Alzheimer’s Plan to coordinate and accelerate the development, testing and approval of new drugs to treat the disease. And the Alzheimer’s Association will soon issue a consensus statement on how to move promising drug candidates like C31 and any BDNF-based compounds to human testing as quickly as possible without putting people at risk of unexpected or unwanted side effects.

Part of the puzzle will include figuring out whether older people should be screened for signs of the disease and when that monitoring should begin. “The idea of applying scans to everyone on their 65th birthday is not going to fly,” says Jagust, noting that amyloid PET scans cost several thousand dollars each. But coming up with some type of risk score, as doctors now do for heart disease, might happen in the near future for Alzheimer’s. It would fold in age, family history, physical activity and other factors. It’s clear now that Alzheimer’s begins decades before symptoms start and that the best treatments will likely begin early, before there is too much damage to reverse.

“Odds are, if you follow anyone in their 70s or 80s for two, three or five years before they pass away and look at their brain under the microscope, you will find two, three or even four of the elements of Alzheimer’s,” Petersen says. That’s why he’s thinking beyond just looking for signs of amyloid and is encouraging his patients to participate in trials testing nonamyloid strategies as well.

“In an ideal world, you want to take a 78-year-old and say, I think in your brain amyloid is contributing to 20% of your cognitive problems, so I’ll give you an anti-amyloid therapy. You also have tau proteins contributing to about 35% of your problems, and so on. You’d want to design a therapeutic regimen based on the different components and their contributions to that patient’s disease,” he says.

C31 may become the first drug in this new Alzheimer’s cocktail; the results of the first studies among 72 healthy people who don’t have any signs of the disease are promising. The next step is to see if it can make any difference in their memory and thinking.

That’s the ultimate test for any Alzheimer’s treatment, and if the history of drug research for the disease is any indication, it won’t be easy. But those aren’t the odds Longo is betting on. He is hopeful. Still frustrated, but hopeful.

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