The announcement came the day before Thanksgiving, but there was nothing in it to be thankful for: An experimental Alzheimer’s drug many thought would slow the disease’s steady cognitive decline had failed to make a significant difference in a massive trial of people with early signs of the illness.
Marty Reiswig took the news hard. “I was just sad,” he says. “I was really hopeful that it would be life-changing for us.”
Reiswig doesn’t have Alzheimer’s disease—he’s a 38-year-old real estate agent in good health. But he is part of a large extended family that’s been afflicted by Alzheimer’s for generations. His Uncle Roy died of the disease. So did Grandpa Ralph. Eleven great-aunts and great-uncles. Dozens of cousins. And now, Reiswig says, “I’ve got a 64-year-old father who’s almost dead of Alzheimer’s at this point.”
His family is one of around 500 in the world with a genetic mutation that means its carriers will develop Alzheimer’s at a much younger age than those without the mutation, for whom the age of onset is typically about 80. For the Reiswigs, those with the gene become sick around their 50th birthday. Other high-risk families can start showing symptoms as early as their mid-30s or, in some cases, their late 20s.
Reiswig decided not to learn his own gene status—there’s a 50-50 chance he inherited his father’s faulty DNA, and he prefers living with the uncertainty. However, he isn’t just idly waiting to meet his fate. Three years ago, he signed up for an innovative drug study that could alter his family’s genetic destiny. Once a month, a nurse comes to his home, inserts a needle in his arm and watches as a bag full of liquid slowly drips into his bloodstream.
As with most trials designed to test whether an experimental drug works—even for diseases that are akin to death sentences—Reiswig might be getting a placebo. But there’s also a chance his monthly infusions include a drug that could stop him, his family members and others like them from losing loved ones to Alzheimer’s. Or, at the very least, delay the disease long enough to give them many more good years, genetics be damned.
The key is early intervention, before symptoms are evident and brain damage is too extensive. “That’s how you stop the disease,” says Rudy Tanzi, director of the Genetics and Aging Research Unit at Massachusetts General Hospital. “You don’t wait.”
Push Back the Onslaught
This aggressive attempt to prevent Alzheimer’s rather than treating it is the most exciting new development in decades, as well as a radical departure for researchers and the pharmaceutical industry. Traditionally, drug companies have tested their therapies on patients who already have memory loss, trouble thinking and other signs of dementia. It’s been a losing tactic: More than 99 percent of all Alzheimer’s drugs have failed tests in the clinic, and the few that have made it to the market only ameliorate some symptoms. Not a single medicine has been shown to slow the relentless progression of the disease.
But with this new approach, even partial success—an appreciable slowing of brain degeneration—could have a big impact, says Dr. Reisa Sperling, a neurologist who directs the Center for Alzheimer’s Research and Treatment at Boston’s Brigham and Women’s Hospital. If a drug therapy can push back the onslaught of dementia by five or 10 years, she says, “many more people would die of ballroom dancing instead of in nursing homes.”
It’s a strategy being tested in five big clinical trials that collectively will cost anywhere from $500 million to a whopping $1 billion. But prevention advocates are confident these studies are a worthwhile gamble. “It sometimes doesn’t feel like it, because we see failure after failure, but we have made huge progress” in learning from mistakes and designing better trials, says Stacie Weninger, executive director of the F-Prime Biomedical Research Initiative and co-chair of the Collaboration for Alzheimer's Prevention, a coalition of leading prevention researchers. “I’m more hopeful now than I’ve ever been that we can stop this disease.”
Success in one or more of these trials matters not only because they may save the lives of the Reiswigs and for many older Americans; they may also save our health care system. Dementia is the most expensive disease to care for, and the number of patients with the condition is expected to explode in the coming years.
Part of the problem with past efforts to tackle Alzheimer’s was that therapies were tested on many people who didn’t even have the disease, because the only definitive way to diagnose Alzheimer’s was through a brain autopsy. That postmortem could reveal the hallmark signs of the disease, but while a person is alive, doctors could make only a best-guess diagnosis—and they were often wrong. That meant Alzheimer’s trials were filled with people who had other types of dementia and were never going to benefit from the therapies. In hindsight, it’s painfully clear the studies were set up to fail.
The past five years have brought two powerful diagnostic tools that help ensure Alzheimer’s therapies are now being given only to Alzheimer’s patients. One involves a kind of brain scan known as positron emission tomography, or PET, while the other requires a spinal tap. Both test for the presence of the toxic amyloid protein that forms the sticky brain plaques thought to be responsible for the disease. “Now, with the right tools, we can match the patient population to the anti-amyloid therapies,” says James Hendrix, director of global science initiatives at the Alzheimer’s Association.
That’s what pharmaceutical company Eli Lilly did in its latest trial of solanezumab, the drug whose trial failure before Thanksgiving had so saddened Reiswig. Lilly had previously tested solanezumab in two huge studies, each involving more than 1,000 presumed Alzheimer’s patients. After those trials ended in failure, however, the company conducted PET scans and realized that up to one-third of its study subjects didn’t have the disease. So Lilly tried again with only people who had confirmed amyloid in their brains. The company also focused on only those with mild forms of the disease. Alas, the third trial was a flop too.
Maybe solanezumab is a bad drug. However, in the trials it did target amyloid as it was supposed to, and it modestly outperformed a placebo by a range of cognitive and functional measures in clinical testing, even if it didn’t meet the threshold needed for marketing approval. That’s why Sperling and others are holding out hope for another explanation: that solanezumab was simply given too far along in the disease process, after irreparable harm has already occurred in the brain. If that’s the case, it might prove more useful if given sooner.
“I’m afraid that even by the stage of very mild dementia, you’ve already lost 70 percent of the key neurons in the memory regions of the brain,” Sperling says. “Ultimately, we need to start treating people before there are symptoms.”
Researchers now know that amyloid starts to accumulate in the brain at least a decade or two before the onset of cognitive problems. This stage of the disease is referred to by experts as “pre-clinical Alzheimer’s,” although few people who qualify for this diagnostic label realize they have a problem. Dr. Jason Karlawish, a geriatrician who co-directs the University of Pennsylvania’s Memory Center, describes this as a “real conceptual shift” in our understanding of the disease. “Someday, you won’t have to be demented to be diagnosed with Alzheimer’s disease,” he says.
What’s happening in this early stage of Alzheimer’s can be likened to the kindling that starts a house fire. Amyloid plaques slowly smolder for years, consuming the neuronal tinder in our brains. By the time dementia kicks in, the fire is raging and it’s too late to save the house. Calling in firefighters at that point is a waste of time and money. You need to dial 911 at the first signs of smoke—and the same could be true of when to deliver anti-amyloid drug therapies.
Hundreds of Billions Lost
Three of the five prevention trials are giving drugs to elderly individuals who are still cognitively normal but have a high chance of developing Alzheimer’s, either because of elevated amyloid levels in their brains or because they inherited a risk-factor gene called APOE4. In either case, the disease is by no means a foregone conclusion for these subjects.
Not so in the other two studies, which focus on those rare kin groups in which doctors know with certainty, because of gene testing, who will develop Alzheimer’s in each family and at roughly what age. One such trial, led by the Banner Alzheimer’s Institute in Phoenix, is being done in Colombia because it includes the world’s largest known family with a mutation that triggers early Alzheimer’s disease. The second study, run by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) of Washington University in St. Louis, includes the Reiswigs and more than 50 other families like them.
“For us, the hope is that we’re going to stave off the damage and delay the onset of symptoms,” says Reiswig’s second cousin Brian Whitney, who knows he carries his family’s Alzheimer’s mutation. At 44, he will soon develop Alzheimer’s if the therapy he’s receiving doesn’t work. His hope for a long life hinges on DIAN-TU.
DIAN-TU’s is a two-in-one study that’s testing a pair of different experimental therapies for their ability to keep Alzheimer’s at bay. Participants don’t know if their getting a placebo or not, but they know which of the two drugs they are receiving otherwise. For Whitney, it’s a Roche drug called gantenerumab, and in Reiswig’s case, it’s Eli Lilly’s solanezumab. Both drugs target the amyloid protein behind Alzheimer’s but do so in different ways: Roche’s gantenerumab breaks up the amyloid plaques that can spur neuron death; Eli Lilly’s solanezumab leaves plaques alone but can mop up free-floating protein to prevent further plaque formation.
Solanezumab thus operates like an outreach counselor who helps take crime-prone youth off the streets of a graffiti-filled neighborhood. If the kids aren’t left to form gangs, they won’t vandalize the area any further. The drug, by eliminating scattered amyloid, stops the deviant proteins from clumping together and forming additional brain-destroying plaques.
That’s the idea, but researchers don’t yet know whether a drug that has failed time and again as a treatment for Alzheimer’s can prevent it. Some experts remain skeptical. They argue that further studies on anti-amyloid drugs are a waste when what is really needed are new therapeutic strategies—and that anyone who still sees promise in solanezumab because it beat a placebo by some tiny amount is guilty of spin and wishful thinking.
“We’re treating asymptomatic people with a drug that has no evidence whatsoever of efficacy,” says Peter Davies, a neuroscientist who directs the Litwin-Zucker Research Center for the Study of Alzheimer’s Disease at the Feinstein Institute for Medical Research. “You might as well give them aspirin.”
But the federal government clearly thinks the trials are worthwhile. In addition to funding from drug companies and philanthropies, taxpayers are ponying up tens of millions of dollars for these trials as part of the country’s national plan to effectively prevent or treat Alzheimer’s by 2025.
The consequences of failure could be dire. Approximately 5.4 million Americans suffer from Alzheimer’s, and if no disease-delaying therapies are found soon, that number is expected to nearly triple by 2050, at which point the cost of treating and caring for all those people could top $2 trillion per year, after adjusting for inflation. That’s up from $236 billion today. O ne in every five Medicare dollars is now spent on people with Alzheimer's and other dementias. In 2050, it will be one in every three dollars. And those figures don’t even include the hundreds of billions more in lost wages for family members who take time away from their jobs to care for loved ones. It’s not a question of a day off now and again. People with Alzheimer’s require around-the-clock care—and more than one-third of all dementia caregivers develop clinical depression.
As Gregory Petsko, director of the Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine in New York City, says, “Pretty much every family is going to have a relative affected by Alzheimer’s, and that’s going to change the way we live, the way we think, the way we plan for our future—everything.”
‘I Can’t Forget Your Face’
Dr. Randall Bateman had no warning the latest solanezumab trial was going to be a failure. He was racing around the house doing chores in anticipation of a big family dinner last Thanksgiving when he received an early-morning phone call on November 23 from executives at Eli Lilly. “I was extremely disappointed,” says Bateman, who leads DIAN-TU. “But I wouldn’t say it was surprising.” He’d been saying prevention has a better shot of success than treatment for years.
Another leading prevention proponent is Dr. Paul Aisen, a neurologist who directs the Alzheimer’s Therapeutic Research Institute at the University of Southern California. In 2014, Aisen teamed up with Sperling for a 1,150-person trial called A4. Short for Anti-Amyloid Treatment in Asymptomatic Alzheimer's, A4 tests solanezumab for prevention. The drug is given to seniors who have no signs of dementia but do have elevated amyloid levels, as measured by a PET scan of the brain. It is looking for changes over a 39-month period in cognitive function, self-care abilities, brain tissue health and other indicators of Alzheimer’s. “We still need to find out what the benefits and risks are” in patients not yet showing symptoms, Aisen says.
The trial asks a lot of its participants. A4 subjects must be willing to come to a hospital once a month for more than three years to receive infusions containing an unproven medicine for a disease they don’t have and might not get. There’s no guarantee of benefit or even safety. And the trial is not particularly remunerative. Some participants can receive up to $2,480 if they complete all the study protocols, including two PET scans, four MRI scans, two spinal taps and 42 infusion visits. But many do not get any compensation, unless you count parking validation.
None of that dissuaded Jerry Blackerby from taking part in A4. “With my family history, I have expected to have Alzheimer’s long before death, and I haven’t yet,” says Blackerby, 82, a retired technical writer whose mother died from the disease, as did her three siblings. “If I’m going to have it, I want to be involved in the study to try to keep others, especially my descendants, from having to go through the hell I’ve seen family members go through.”
Last December, Blackerby drove more than 100 miles from his home in southern Oklahoma to the University of Texas Southwestern Medical Center in Dallas to receive his first infusion. He will make this same four-hour round-trip trek every month for the next three years.
For Don, a retired insurance agent, the motivation to participate in A4 was his partner, Fran. He first noticed her Alzheimer's four years ago when he arrived at her house expecting a dinner of meat stew, only to find a near-empty pot. “She had remembered the onions,” he recalls. “But she had forgotten everything else.”
Don (who asked that his last name not be used because he didn’t want to come across as self-promotional) tried to enroll Fran in A4, but her disease was too far advanced. Only he was eligible—a PET scan showed he had the hallmark amyloid logjam in his brain. He started getting infusions last fall at Brigham and Women’s Hospital in Boston.
On a rainy day in late November, Don, with a plaid-blue shirt sleeve rolled up past the elbow and an IV catheter in his right arm, reminisced about meeting Fran nine years ago at a singles dance at Vincent’s Nightclub in the suburbs south of Boston. He’s mild-mannered and surprisingly youthful for a 76-year-old, gray-haired grandfather who raised six children on his own after his wife died in a car crash 33 years ago. He beams when he talks about Fran retaining her sense of humor and ability to play tennis, but he turns solemn when he describes how it took four tries to explain to her why he was going to the hospital today. “She knows,” he says, “but she forgets.”
While he’s talking, a nurse comes to deliver the saline flush that always follows Don’s infusion. She introduces herself, although Don recognizes her from a previous visit. “I can’t forget your face,” he says. “I told you, ‘You look just like my cousin.’”
The amyloid in Don’s brain has clearly not impaired his memory, but it’s there. And perhaps the therapy he is receiving will halt further damage. Or perhaps he will suffer the same fate as Fran. “I worry for myself. I worry for my kids. But I try not to think too much about that,” he says. “Right now, I have too many obligations.”
Good Genes in Norway
Aisen, the A4 investigator, is optimistic about solanezumab as a preventive medicine. In announcing the failure of the drug for symptomatic Alzheimer’s at a major scientific meeting late last year, he told a room full of doctors, neuroscientists and drug executives, “I expect the treatment effect to be larger in an earlier stage of disease.” Results of the A4 study will be known in 2020.
Until then, Eli Lilly is continuing to support A4 and DIAN-TU, the two prevention trials that include solanezumab, but the company has already signaled that it plans to focus on other therapies. Many academics in prevention research are beginning to consider other drugs too. They are still committed to prevention; they just want to determine which of the anti-amyloid drugs works best.
Last December, Bateman and his collaborators announced they were adding a third drug to the DIAN-TU study, one that blocks the beta-secretase enzyme responsible for producing amyloid. Also, Aisen and Sperling recently launched a huge prevention trial, called EARLY, which is administering that same beta-secretase-targeted drug to people who, as in A4, are healthy but have elevated amyloid in their brains.
Just this month, a late-stage trial of a different beta-secretase inhibitor, one from Merck, was halted early after experts determined that the drug had no chance of helping Alzheimer's patients who already showed symptoms of the disease. Dr. Roy Twyman, head of Alzheimer’s drug development at Janssen, a division of Johnson & Johnson and the manufacturer of the beta-secretase inhibitor in the EARLY and DIAN-TU trials, is confident that prevention with this type of agent should work, and he points to a study from Iceland as evidence that the strategy should work. Five years ago, researchers there discovered the first known gene mutation that protects individuals against Alzheimer’s. It’s extremely rare, found in less than one in 200 people from Nordic countries. Yet those who carry the mutation are about five times more likely to reach their 85th birthday dementia-free.
And what does that mutation do? It impairs the ability of beta-secretase to do its job. “Nature has already taught us a lesson in humans,” says Twyman—and it’s one that J&J hopes to take to the pharmacy shelf.
Another beta-secretase inhibitor, from Novartis, is one of two drugs included in a prevention study, the Generation trial, run by Dr. Eric Reiman and his colleagues at the Banner Alzheimer’s Institute. That study, like A4 and EARLY, is being done with cognitively normal older adults at risk of developing Alzheimer’s. But rather than looking for signs of amyloid accumulation, the Generation trial involves volunteers who inherited two copies of APOE4. That increases their odds of developing Alzheimer’s about fifteenfold, compared with the general population.
An estimated 2 percent of the population has two copies of APOE4, but few in that select group know it. It hasn’t been worth getting tested for this gene because there was little you could do with the results. “Really, for the first time, what to do about it is different,” says Dr. Pierre Tariot, the Banner Alzheimer’s Institute’s director. “You can choose to participate in a trial.”
What Do You Mean I’m Not Covered?
If the drugs prove to be effective at preventing Alzheimer’s, their success will immediately raise another urgent question: Who’s going to pay for them?
Prevention proponents envision a day in which everyone above a certain age—say, 50—would get screened regularly for molecular and genetic risk factors for Alzheimer’s. If they test positive, they could start taking a preventive medicine, much as those with high cholesterol today can pop a daily statin to ward off a heart disease. “We will eventually think about treating a much broader population,” says Sperling.
But statins cost pennies a pill. Any new Alzheimer’s drug would likely cost tens of thousands of dollars per year. Insurance companies may balk at paying that for seemingly healthy individuals, especially because not everyone with elevated amyloid or APOE4 will develop dementia.
Howard Fillit, chief science officer of the Alzheimer’s Drug Discovery Foundation, thinks researchers should focus on treating people with symptoms but halting the disease at the pre-dementia stage when only mild cognitive impairment is evident. Problems with memory, thinking and judgment at that point are more pronounced than for those who experience normal, age-related “senior moments.” But most people with MCI are not so far gone that they require constant care. They can keep living independently.
“MCI is the sweet spot in terms of the cost of trials, the cost of drugs and quality of life for patients,” Fillit says. “That’s still prevention because you’re preventing dementia.”
Anyone who’s ever had a spouse get lost coming home from the grocery store or a parent unable to write a check might disagree. And so many researchers continue to dream of a time when they can prevent all cognitive impairment. To that end, they plan to start testing drugs even earlier in the disease process, before any amyloid has started to damage the brain. For example, Aisen and Sperling will soon launch a placebo-controlled trial involving people who weren’t eligible for the A4 or EARLY trials because their amyloid levels didn’t reach the threshold for inclusion. And Dr. Eric McDade, a neurologist involved with DIAN-TU, plans to start treating people with the sure-thing, genetic form of Alzheimer’s—families like the Reiswigs and others—even sooner than the current trials allow. “Going as early as possible is really the goal,” McDade says.
Developing drugs to prevent Alzheimer’s disease could be a discovery of Nobel proportions. There is no guarantee the current trials will succeed, but researchers believe they are getting close to solving what had, until recently, seemed to be one of medical research’s toughest challenges.
“It’s an exciting time for us,” says the Banner Alzheimer’s Institute’s Reiman. “The hope is that we already have a treatment that can substantially reduce the risk of Alzheimer’s. But there’s only one way to find out, and that’s through these trials that chart new territory.”