Why Is It So Hard to Treat Alzheimer’s?

Why is this so difficult?

Across the pharmaceutical industry, up to 90 percent of all experimental medicines that reach clinical trials don’t make it to market, either because they don’t work or they have bad side effects. Alzheimer’s drug research has an even higher failure rate. From 2004 to mid-2021, 98 experimental Alzheimer’s drugs failed in later-stage human studies. More were abandoned in labs or early human trials. Not a single new drug for Alzheimer’s was approved by the FDA for nearly 18 years. Among the research community, “people were despondent; it was like a clinical depression across the field,” Bateman says.

One major obstacle has been the historical difficulty of diagnosing Alzheimer’s. Brain scans have shown that 17 to 22 percent of participants in Alzheimer’s studies in the recent past did not have amyloid plaque and may not have actually had the disease. And 36 percent of failed phase 3 drug trials from 2004 to 2021 didn’t test participants for the presence of amyloid plaques or tau tangles, another hallmark of the disease, meaning their cognitive problems could have been due to something else. 

“You’re never going to get a positive result when you’ve got the wrong people in the trial,” says Catherine Mummery, head of clinical trials at University College London’s Dementia Research Centre.

Another major issue: Researchers may have been too narrowly focused on one culprit. One-quarter of the failed drugs were aimed at amyloid plaques — globs of protein in the brain that were first spotted 117 years ago by German psychiatrist Alois Alzheimer in the brain of a woman with severe dementia. Since these sticky blobs were the defining feature of the disease, it made sense that they were the primary target of researchers.

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“The reason we’ve been so focused on plaques for so long is that they really stand out as soon as you look at the brains of people with Alzheimer’s disease,” says Kyle Travaglini, a scientist at the Allen Institute for Brain Science in Seattle, where he is part of a team creating an atlas cataloging how thousands of different types of brain cells are changed in Alzheimer’s disease. “You see these giant, ugly balls all over the brain. It wasn’t unreasonable to look at them initially.” 

Yet drug after drug developed to target the amyloid plaques — most notably aducanumab, an earlier drug similar to lecanemab that was recently discontinued — failed to show any clear impact on the cognitive decline of patients. Lecanemab is the first to show even modest success. Donanemab, which also clears amyloid plaques and slows disease progression, is expected to receive full FDA approval this year. And researchers are beginning to look at using focused ultrasound to open the blood-brain barrier and amp up the effectiveness of anti​amyloid drugs. In January, a West Virginia University study of three people that combined focused ultrasound with drug infusions removed more amyloid than the drug alone.

New approaches, new hope

Other theories about what triggers Alzheimer’s are getting more attention — and drugs that target culprits other than amyloid are moving into early- and late-stage human trials. In 2016, 56 percent of disease-modifying Alzheimer’s drugs in human studies were aimed at amyloid plaque. By 2023, of 141 treatments in human trials, 84 percent were not for ­amyloid. Fillit says the intensity and variety of research — and lessons learned during years of frustration — should lead to faster progress.

Targeting amyloid is significant, he says, “but it’s not the whole story.” There’s a growing consensus that several factors might work together to cause the disease. Researchers continue to study amyloid plaques, but other human trials are underway on drugs designed to reduce brain inflammation, protect synapses (parts of brain cells that communicate with each other) and improve aspects of brain metabolism (such as processing blood sugar, the brain’s preferred fuel).

In particular, researchers are taking a harder look at tau tangles, globs of protein that form inside the brain cells themselves. One medicine attracting a lot of attention is called BIIB080. In a trial led by Mummery at the University College London, it was the first anti-tau drug to successfully remove these damaging protein tangles from brain cells in a human study.

“Tau tangles in the brain seem to mirror much closer to the cognitive symptoms people have,” Bateman says. “A lot of us think that’s a clue. If we could neutralize tau, people’s symptoms could be better managed.”

At the University of California San Francisco (UCSF), a study called the Alzheimer’s Tau Platform recently won a $151 million grant from the National Institutes of Health (NIH) to test two anti-tau drugs plus an anti-amyloid drug that will be given together to 900 people with early-stage disease. “At a certain point with amyloid accumulation, tau gets sparked like a forest fire that really starts to do damage,” Mummery says.

On a different front, Finnish researchers launched a study that combines brain-healthy lifestyle steps with metformin, a diabetes drug that might improve blood sugar processing in the brain. The study will look at the effects of lifestyle plus the medication in people at risk for Alzheimer’s and dementia who do not have thinking and memory problems.

“The brain is only 3 percent of body weight but uses 20 to 25 percent of the body’s energy, mostly from glucose,” Fillit explains. Trouble absorbing blood sugar, called insulin resistance, increases with age. “If the brain is deprived of energy, neurons can die,” says Fillit, whose foundation helps fund the study. “We want to see if the combination would have more benefit than either one alone.”

Having drugs against these various factors, Fillit says, means that within 10 years, customized, multidrug treatments will likely be prescribed based on a simple blood test. (An analogy would be our approach to treating heart disease, which might involve cholesterol medications, blood pressure pills, blood sugar controls, dietary changes or a combination of these treatments.)

“We are starting to give combination drugs in trials,” Mummery says. “I believe that in 10 years’ time, we will have blood biomarkers that give a fingerprint of what your disease looks like. We’ll be able to use that to define an individualized treatment regime. We’ll be thinking about brain health in terms of prevention more than just dementia symptoms.

“I’m an optimist,” she adds. “We have a foundation. Once you have that foundation, research can accelerate.”

Is your brain on fire?

“I’ve always been intrigued by inflammation,” says Linda Van Eldik, director of the Sanders-Brown Center on Aging and the Alzheimer’s Disease Research Center at the University of Kentucky in Lexington. She says chronic inflammation may be one of the primary drivers of Alzheimer’s.

Van Eldik studies microglia, immune cells that patrol the brain by the tens of billions. Normally they work like trash trucks, gobbling up little scraps of amyloid protein waste before it can cause trouble. But when overwhelmed by inflammation, microglia pump out a torrent of inflammatory chemicals called cytokines. “Cytokines damage nerve cells [neurons] and synapses, reducing communication between cells,” she explains. It’s a vicious cycle. When cells are damaged by cytokines, microglia “start producing more inflammation, you get more damage, then you get more inflammation,” Van Eldik says.

This may explain why aging, head injuries, stroke and other brain insults increase risk for Alzheimer’s and other dementias, she says.

Van Eldik’s NIH-funded research includes versions of an anti-inflammation drug candidate that blocks microglia from overproducing inflammatory compounds without stopping their normal trash-collection duties, she says. In phase 1 clinical studies, the drug was found to be safe in healthy adults. It is currently being tested in people who had strokes caused by brain bleeding and with brain cancers treated by radiation. If successful, Van Eldik expects the drug will be tested next in people with Alzheimer’s. She also expects it to be used in other cell-damaging brain conditions in which abnormal inflammation plays a role. “This drug has the potential to be a first-in-class disease-modifying therapy for Alzheimer’s disease and related dementias,” Van Eldik says.

Controlling neuroinflammation is at the forefront of new treatment ideas for Alzheimer’s, Fillit agrees. In 2023, there were more drugs in human trials for inflammation than for any other Alzheimer’s disease–modifying factor, and Fillit says inflammation drugs could be among the first Alzheimer’s compounds to win FDA approval in the next three to five years.

The battle on the home front

The difficulty in diagnosing Alzheimer’s accurately has long hindered scientists’ ability to study the disease. Historically, it could be confirmed only by examining the brain after death. Today researchers can make a firm diagnosis of Alzheimer’s by spotting amyloid plaque via positron emission tomography (PET) or by testing for its presence with a lumbar puncture, says Ronald Petersen, M.D., a Mayo Clinic neurologist and Alzheimer’s researcher. “But the first one is expensive. And the second one is invasive.” So they’re not routinely used.

New and on-the-horizon blood tests that measure amyloid and tau in the brain aid researchers in tracking brain changes during studies. These blood tests are beginning to be used in doctors’ offices. Sperling expects tests to be available in the next year showing not just how much amyloid is in the brain but whether it is triggering the explosion of tau that seems to torpedo thinking and memory. This could help, in the future, determine risk in people who do not have Alzheimer’s symptoms. “We’re going to do a much better job of predicting individual risk,” she says.

That’s significant not just for treatment but in terms of prevention as well. For all the deep science that surrounds the war on Alzheimer’s, one of the most important weapons against the disease remains the simplest: healthy living. In that way, late-life Alzheimer’s resembles heart disease, diabetes and many other chronic conditions linked to aging: There is a genetic component, yet so much of prevention is in our own hands. 

A 2022 University of Minnesota study found that an estimated 41 percent of Alzheimer’s and related dementias were attributed to a dozen modifiable risk factors, of which high blood pressure, obesity and physical inactivity had the most impact.

“People need to know, ‘What are my risk factors for Alzheimer’s and other dementias, and are they things I can do something about?’” says Kristine Yaffe, M.D., director of the Center for Population Brain Health at UCSF. Yaffe was the lead researcher on a November 2023 study of 172 adults ages 70 to 89 who had two or more risk factors for dementia. Those who worked on one or more personally chosen risk factors for two years boosted their scores on tests of thinking and memory and lowered their dementia risk more than those who simply received educational materials.

“Instead of a one-size-fits-all program, we wanted to see what would happen if we personalized it,” Yaffe says. Strategies included taking care of high blood pressure, diabetes and/or depression; exercising; getting sound sleep; socializing; and quitting smoking.

Dean Ornish, M.D., founder of the nonprofit Preventive Medicine Research Institute and clinical professor of medicine at UCSF, is directing the first randomized controlled trial to determine if the same lifestyle changes that he pioneered to reverse coronary heart disease might slow, stop or reverse the progression of mild cognitive impairment due to Alzheimer’s disease. 

“What’s good for your heart is also good for your brain, because they share many of the same underlying biological mechanisms,” Ornish says. “We’re at a state of evidence with Alzheimer’s similar to where we were 45 years ago with coronary artery disease. At that time, it was thought that heart disease could only get worse. We found that bigger lifestyle changes could often reverse the progression of heart disease. We are studying if the same may be true for mild cognitive impairment due to Alzheimer’s disease as well. One man shared, ‘I have a sense of hope.’ ” UnDo It!, a book Ornish wrote with his wife, Anne, describes his lifestyle medicine program for both heart disease and Alzheimer’s.

Prevention studies using drugs are gearing up. Researchers study medications like lecanemab in people with early evidence of Alzheimer’s brain changes who do not yet have life-changing thinking and memory problems. In the future, Sperling says, drugs could be started before memory troubles appear — the way people with high cholesterol take statins to lower risk for a heart attack and those with diabetes take blood-sugar-lowering drugs to protect against complications such as kidney disease.

“This is the way forward,” she says. “It’s exactly what we do in heart disease and diabetes. We lower cholesterol before someone has a heart attack. This is what we have to do in Alzheimer’s disease.

“For the first time, it’s very feasible.”