On the past two years, observing the world of Alzheimer’s research from the outside has been like driving without a seatbelt over an uneven mountain road. The first novel Alzheimer’s medication in nearly two decades, Aduhelm, was approved for sale in 2021 by the US Food and Drug Administration, which unusually overruled its advisory committee to do so. The medication was made to function by removing amyloid beta buildups from patients’ brains, a protein long associated with the illness. The drug did remove amyloid in clinical trials, but the committee decided against recommending it because there was no evidence that it improved cognition.
Alzheimer
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.
The “amyloid hypothesis” was suddenly being deconstructed by journalists throughout the nation for their readers in an effort to understand why the FDA would approve a medicine without proof that it decreased symptoms—and why that decision sparked such controversy. The narrative went as follows: Since amyloid beta plaques, which are collections of misfolded amyloid beta protein, are thought to be hazardous to neurons, many scientists have held this belief for decades. Despite the repeated failures of amyloid-targeting medications that, according to the amyloid hypothesis, should have worked, critics claim that the amyloid camp has long maintained a hegemonic hold on the field, driving out other views. Then, in 2022, Science detailed accusations of substantial and pervasive dishonesty against one amyloid researcher.
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.
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