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Friday, May 24, 2024

For Alzheimer’s Scientists, the Amyloid Debate Has No Easy Answers

Watching the Alzheimer’s research world from the outside over the past two years has felt like a car ride over an unpaved mountain road without a seatbelt. In 2021, the US Food and Drug Administration took the unusual step of overruling its advisory committee to approve the sale of Aduhelm, the first new Alzheimer’s drug in nearly two decades. The drug was designed to work by clearing accumulations of amyloid beta, a protein that has long been linked to the disease, from patient’s brains. In clinical trials, the drug did remove amyloid—but it didn’t convincingly improve cognition, so the committee recommended against it.

But the FDA determined that amyloid clearance was enough, and it gave Aduhelm accelerated approval. The decision was wildly controversial—it prompted internal and congressional investigations, and three members of the advisory committee resigned.

Suddenly, journalists across the country were scrambling to break down the “amyloid hypothesis” for their readers, in order to explain why the FDA would approve a drug without evidence that it reduced symptoms—and why that decision provoked so much debate. The story went like this: For decades, many scientists have believed that Alzheimer’s disease is caused by amyloid beta plaques, clumps of misfolded amyloid beta protein, possibly because these plaques are toxic to neurons. Dissenters have argued that the amyloid camp has long maintained a hegemonic hold on the field, forcing out alternative theories—despite the repeated failures of amyloid-targeting drugs, which, according to the amyloid hypothesis, should have worked. Then in 2022, Science outlined allegations against one amyloid researcher accused of serious and systematic dishonesty, reinforcing concerns that the amyloid hypothesis was a dubious proposition promulgated by fraudsters.

This September, the ride took another turn with the release of preliminary results from the Phase 3 trial of lecanemab. Like Aduhelm, lecanemab is an antibody that targets amyloid beta, and it was developed by the same companies. But this time, the drug did measurably slow cognitive decline in a clinical trial of almost 2,000 people with early-stage Alzheimer’s. In general, everyone’s cognition got worse over the course of the trial, but those who got the drug experienced less decline than those who received a placebo. The difference was small: After 18 months, patients on lecanemab saw only half a point less of decline on a standardized cognitive scale that operates in half-point increments.

After so much hemming and hawing about the amyloid hypothesis, this new drug would seem to have proved it—lecanemab cleared amyloid beta from people’s brains, and the progression of their disease slowed. In the research world, though, the story hasn’t been nearly so black-and-white. After years of failed drugs, Alzheimer’s scientists are excited that something might finally have worked, if only modestly. But the implications of the trial are complicated—partly because the amyloid hypothesis itself isn’t nearly as straightforward as it may seem.

“By and large, people would say amyloid is important. I don’t think anyone is saying that amyloid isn’t important,” says Eleanor Drummond, Bluesand senior research fellow at the University of Sydney. The question, she says, is “whether it’s the be-all and end-all”—enough to justify a drug approval with little other evidence of benefit, and enough to dominate the search for a cure for Alzheimer’s.

At this point, no one believes that amyloid is all there is to Alzheimer’s. Some researchers subscribe to the “amyloid cascade” theory—the idea that amyloid accumulation sets into motion a sequence of neurological insults, the way a lit cigarette starts a forest fire. Tau proteins, which form “tangles” in the Alzheimer’s brain much like amyloid beta forms plaques, and neuroinflammation, or activation of the brain’s immune system, have both birthed their own fruitful subfields.

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Even the most ardent amyloid advocates interpret the lecanemab results in light of this complexity. In an interview with WIRED, Dennis Selkoe, one of the most visible proponents of amyloid and a professor of neurologic diseases at Harvard Medical School, enthused about the possibility that lecanemab might also lower tau levels. And Mychael Lourenco, an assistant professor of medical biochemistry at the Federal University of Rio de Janeiro who describes his work as “based on the amyloid hypothesis,” doesn’t claim any great victory on the basis of the lecanemab announcement. His response? “It tells me that the amyloid hypothesis is not as wrong as some people would say.”

And on the other side of the fence, George Perry, a professor of neuroscience, and developmental and regenerative biology at the University of Texas at San Antonio and a well-known amyloid critic, nevertheless says he believes that amyloid plays a role in Alzheimer’s. “I don’t buy the amyloid cascade, but I don’t buy the amyloid being irrelevant,” he says.

Part of the reason for this apparent détente may be the ambiguity of the phrase “amyloid hypothesis.” Pretty much everyone believes that amyloid has some link to Alzheimer’s—mutations in genes like presenilin and amyloid precursor protein, which play major roles in the generation and processing of amyloid, cause early-onset Alzheimer’s with near certainty. Simultaneously, no one holds the view that Alzheimer’s is only a matter of amyloid plaques—otherwise, the lecanemab results should have been much more impressive. Much of the debate seems to center around whether amyloid can be considered the root cause of Alzheimer’s. And clinical trials are of limited help in answering that question.

Unlike many other scientific experiments, drug trials are slow and infrequent, and they are not typically repeated. It can be nearly impossible to determine why a trial succeeded or failed, especially if the trial was poorly designed or executed—as some researchers say has been the case with trials of many Alzheimer's drugs, especially Aduhelm. Over a dozen anti-amyloid drugs have failed in human trials; most recently, on Monday, Roche announced that two trials of its drug gantenerumab did not slow clinical decline in people with early-stage Alzheimer’s. One possibility could be that amyloid plays only a small role in most cases of Alzheimer’s disease. Or perhaps the patients in the trials were too far along in their disease progression. Or maybe the drugs didn’t actually clear amyloid at all—few trials had directly tested for an impact on amyloid plaques before the Aduhelm trials.

Scientists will get a closer look at the lecanemab data when researchers present them at the Clinical Trials in Alzheimer’s Disease conference later this month. If the originally reported results hold up under scrutiny, they would seem to show that amyloid plays at least some role in the cognitive deficits of Alzheimer’s. More enticingly, they would suggest that anti-amyloid therapies might not be a complete dead end. But that doesn’t necessarily have much bearing on outcomes for those contending with Alzheimer’s disease today. The study “is a winner in the sense of drug development and antibody development,” says Lon Schneider, a professor of psychiatry and the behavioral sciences at the University of Southern California. But “it still is really an open question of whether, in the end, patients and families will see this as helpful.”

The question for many scientists, then, is how to make those therapies better. Rudolph Tanzi, a professor of neurology at Harvard Medical School, hopes to find an amyloid-targeting treatment that can be used as a preventative before any symptoms appear, much like statins are used to reduce the risk of heart disease. Others think that a multi-drug approach that simultaneously targets other components of the disease, like tau and neuroinflammation, will be necessary.

It’s possible that the promising lecanemab results will shift Alzheimer’s drug development farther toward amyloid and away from those other possibilities. Drummond says she feels some trepidation at that prospect. “In the past, all the funding eggs have been in the amyloid basket. We don’t want that to happen again,” she says. There’s no guarantee that such an approach will lead to better results than the marginal slowing of cognitive decline shown in the results made public so far. “It’s probably a good drug, if it does what they say it does,” Drummond says. “But I think we can still do better.”

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