In November of 1901, a young German psychiatrist and neuroanatomist, Alois Alzheimer, found what appeared to be misfolded proteins forming sticky clumps, or plaques, between the neurons in the brain tissue of a patient who had died from dementia. Inside the neurons he found threadlike twists, called neurofibrillary tangles, of another protein. Eventually these plaques and tangles came to define the disease named after him: Alzheimer’s disease.
By the mid 1980s, these strange proteins had been identified as beta-amyloid proteins, and by the 1990s it was widely accepted that an excess of these proteins caused the formation of the plaques, which in turn caused the disease. The tangles, which turned out to be malformed strands of a protein called tau, were thought to be a result of the amyloid plaques. For the past 30 years, the bulk of research on Alzheimer’s, and most of the efforts to find a cure, have been based on the amyloid hypothesis.
However, after decades of research based on this hypothesis, drug trials have mostly struck out. No drug tested has produced meaningful improvement in the symptoms of the disease. Even drugs that reduce amyloid levels in the brain haven’t done what really matters: improve the lives of people with Alzheimer’s disease.
In January of this year, a new Alzheimer’s drug, lecanemab, was approved by the FDA even after the deaths of several trial participants raised questions about the drug’s safety. Safety issues aside, lecanemab is far from a cure. It did not stop the progression of the disease, and it reduced cognitive decline by only a small amount. “It’s a small step in the right direction,” says Donald Weaver, MD, PhD, clinical neurologist and Alzheimer’s researcher at the University of Toronto, “not a big stride.”
Are We in a Rut?
These disappointing results have led many researchers to ask if the amyloid hypothesis needs rethinking. Marissa Natelson Love, MD, is a neurology researcher at the Heersink School of Medicine at the University of Alabama at Birmingham. Natelson Love has focused her research on anti-amyloid therapies based on the amyloid hypothesis and is recruiting patients for further studies on lecanemab. Still, she says, “Every time we have a meeting, someone asks, ‘Are we on the wrong track?’” Perhaps, as Weaver once put it, Alzheimer’s research is in an “intellectual rut.”
There’s a reason science sometimes gets in these ruts. Science is a slow, accretive process that builds upon work — often decades of work — that came before.
Researchers complete PhDs on a particular topic, then go on to be postdocs in the lab of an established scientist in the same area. Soon there’s an entire body of researchers with years of training and experience in one approach to a given problem, explains Michael Strevens, PhD, philosopher of science at New York University. “There’s a protocol, what you might call a recipe book, for doing the science. Whereas with a new, untested hypothesis, no one has yet written the recipe book.” This isn’t laziness, but momentum. Like a giant ocean liner, research can’t turn on a dime. When it comes to Alzheimer’s, the momentum is mostly behind the amyloid hypothesis. The roles of other processes in the course of the disease, such as inflammation, prior infections, or autoimmune illness, have gotten short shrift.
Still, we shouldn’t throw the baby out with the bathwater. The problem may not be with the amyloid hypothesis, but with the specific drugs being tested. Maybe researchers just haven’t found the right drug. Or maybe these are the right drugs and they’re just being given at the wrong time; it could be that in order to be successful, anti-amyloid treatments need to start long before symptoms appear.
Another possibility is that the selection of trial participants has not been ideal. Until the past decade or so, Alzheimer’s couldn’t be definitively diagnosed until after death. “If we go back and look at the autopsies from previous Alzheimer’s disease studies,” says Natelson Love, “not everyone in the study actually had Alzheimer’s.” Not only might that explain why a particular trial was unsuccessful, but it could also have a downstream effect on future research. If researchers were unknowingly testing a potential Alzheimer’s treatment on patients who didn’t have Alzheimer’s, that data would be flawed — and later research that drew on it could be flawed, too.
New techniques make it possible to diagnose Alzheimer’s before death. Imaging tests like MRI can rule out other reasons for memory loss; specialized PET scans can detect beta-amyloid plaques and tau proteins. Cerebrospinal fluid can now be tested for biomarkers of amyloid and tau, and though not yet widely available, some new blood tests can detect the presence of amyloid. While these techniques are not enough to diagnose the illness alone, they are making it much easier to confirm it in living patients.
Traffic Jams in the Brain
New approaches to studying amyloid plaques might also change the trajectory of Alzheimer’s research. Rather than just trying to rid the brain of plaques and tangles, researchers are now investigating the biological pathways that created them in the first place. As Scott Small, MD, director of the Alzheimer’s Disease Research Center at Columbia University, put it, “One of the reasons there’s been such frustration is because we haven’t yet fully understood what’s fundamentally broken in Alzheimer’s, what’s fundamentally wrong. If you don’t know what’s fundamentally broken, you can’t fix it.”
Though Small says he has great respect for the amyloid hypothesis, he agrees that clearing plaques, while beneficial, results in only “subtle slowing of cognitive decline.” If you want to have a meaningful impact on the illness, he says, you need to get to the actual source of the pathology by addressing the cellular biology of the disease. He and his colleagues are pursuing that approach, looking for the source of the problem at the cellular level and trying to discover what is happening inside neurons to create the problems between neurons.
Small and others are seeking the source of the problem in endosomes, organelles inside cells that regulate the movement of proteins. Proteins on their way out of the endosomes get blocked, creating what Small calls “traffic jams,” eventually leading to the buildup of amyloid and tau proteins and thus to Alzheimer’s. They’re working on therapies that would unjam endosomes.
Meanwhile, a variety of other approaches to the problem are gaining traction. Weaver’s lab in Toronto is working on the hypothesis that Alzheimer’s disease is an autoimmune disorder in the brain. The hypothesis is that amyloid is not an abnormal protein, but a normal component of the brain’s immune system, produced in response to bacterial infections. The problem, as with all autoimmune illnesses, is that something goes wrong with the immune system, causing it to attack the body’s own tissues; in this case, the amyloid confuses healthy brain cells with infectious bacteria and attacks brain cells instead of or along with the bacteria. The result, of course, is Alzheimer’s disease. Because the drugs used to treat autoimmune illness in other parts of the body do not have a therapeutic effect in the brain, Weaver and colleagues are researching drugs that target the immune pathways specifically in the brain.
Other researchers are looking into possible connections between infections and the inflammation associated with Alzheimer’s. Kristen Funk, PhD, a neuroimmunologist at the University of North Carolina, Charlotte, studies how the body’s inflammatory response to viral infections, such as herpes simplex and viral encephalitis, affects cognition and might be linked to the development of Alzheimer’s.
Some evidence suggests that Alzheimer’s could be a metabolic disorder, much like type 2 diabetes. In fact, some researchers have called Alzheimer’s “diabetes of the brain” or “type 3 diabetes.” Insulin resistance in the brain can lead to inflammation and oxidative stress, and eventually to amyloid plaques and Alzheimer’s. Bolstering this theory are findings that some diabetes drugs may reduce the risk of Alzheimer’s.
Alzheimer’s takes a long time to develop. The damage to the brain that eventually results in the disease can begin 20 or even 30 years before memory loss or other symptoms. In a way, that’s a cause for hope: if we could only figure out how to stop it or slow it down, we’d have so much time to do it. Epidemiological studies, studies that look at who gets Alzheimer’s and when, offer some hints about prevention. Those studies suggest that although the end result is amyloid plaques in the brain, the disease could actually be caused by a number of factors at once.
While genetics certainly plays a role, some of those risk factors are modifiable: obesity, diabetes, cardiovascular disease, high cholesterol, high blood pressure, hearing loss, and depression are some known ones.
As more evidence suggests that modifying those risk factors can prevent — or at least reduce the risk — of Alzheimer’s, many researchers are looking at what they call a multimodal approach to prevention. Lifestyle interventions, like an improved diet and more exercise, reduce the risk of cardiovascular disease and diabetes. Existing medications that control blood pressure, cholesterol, and blood sugar, for example, become a key part of this approach to prevention. Something as simple as fitting a patient with hearing aids or addressing their loneliness and isolation might be effective as well.
The beauty of these interventions is that they’re mostly low risk. Treatments for the risk factors for Alzheimer’s have already been in constant use for years. They’re likely to be relatively inexpensive and are typically covered by Medicare and other insurance plans. Lecanemab, on the other hand, is expected to cost more than $25,000 per year.
“Who can afford that?” asks Weaver. “Is it going to be restricted to wealthy people in wealthy countries? Ultimately, I hope that somebody comes up with an agent which is cost-effective to produce, cost-effective to distribute, and therefore may actually have a global impact on this disease.”
Most researchers agree that the final answer will likely involve a combination of approaches. “I think, just like in cancer, [Alzheimer’s treatment] is eventually going to be a cocktail that will bolster people’s resilience to the breakdown of the nerve cells, as well as remove some of the things triggering it,” says Love.
Any real hope for a cure for Alzheimer’s likely rests not on any one hypothesis, but with the willingness of scientists to question themselves, each other, and their prior assumptions. That doesn’t mean the years spent with a laser focus on amyloid have been wasted. But researchers do agree that it’s time to look more closely not only at the amyloid paradigm, but also further afield, in the hope of finally making progress against this devastating illness.
