And well, the amyloid hypothesis is not dead yet. Large clinical trials targeting amyloid are still underway—either using new, potentially more powerful anti-amyloid drugs or trying out the previously failed drugs in patients with less advanced Alzheimer’s. These trials will likely affirm the amyloid hypothesis or kill it for good.

With the benefit of hindsight, the story of the amyloid hypothesis will be written either as one where scientists soldiered on despite setbacks, or one where a wrong idea derailed a field for 25 years. And the field of Alzheimer’s research is no stranger to ideas inflated, abandoned, and sometimes resurrected.

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In the 1980s, the importance of amyloid was not the dominant idea in a field that might need shaking up. It was the upstart idea doing the shaking up. At the time Alzheimer’s researchers were considering the cholinergic hypothesis, which posits that a decline in the neurotransmitter acetylcholine is a cause of the disease. The handful of available Alzheimer’s drugs come out of this line of research. But it never produced an outright cure, and lack of acetylcholine has since been abandoned as a root cause of Alzheimer’s.

Dennis Selkoe—who is now a leading proponent of the amyloid hypothesis and a neurologist at Harvard—was not that interested in acetylcholine at the time either. He actually started out studying the buildup of tau protein, which is behind yet another hypothesis for the cause of Alzheimer’s. But he moved on to the nascent amyloid field when he met George Glenner, who was gathering data on how amyloid can build up into waxy plaques throughout the body. Amyloid deposits in the kidneys can cause kidney failure; in hearts, it can cause heart failure. Wouldn’t it follow then, that amyloid deposits in the brain can cause brain failure? The apparent a-ha moment came in 1984, when Glenner indeed found the protein in the brain tissue of Alzheimer’s patients and purified it. (Glenner himself had systemic senile amyloidosis, where amyloid builds up in the body. He died in 1995.)

Selkoe’s lab eventually worked out some of the molecular mechanisms behind the amyloid build-up. Then, geneticists found that people with a family history of Alzheimer’s also had mutations in the very genes that encode for making amyloid. “The genetic evidence is so strongly supported,” says Selkoe, “People gravitated toward it.” A 1992 paper in Science by John Hardy and Gerald Higgins laid out the case for the amyloid hypothesis.

The discovery of these genes created a sense of optimism in Alzheimer’s research. Scientists had a roadmap to a cure. Drug companies just needed to follow it. But of course, a quarter century later, there are still no drugs for Alzheimer’s that target amyloid.

“When you have a setback, there’s understandably questioning, are you sure about the science,” Selkoe says about the latest Merck trial. But he remains convinced that targeting amyloid could still succeed with a few changes—like when patients start treatment. By the time an Alzheimer’s patient starts suffering memory loss, that may be too late. So the A4 trial, coordinated out of the University of Southern California, is testing an previously unsuccessful drug in patients with elevated amyloid levels but no outward cognitive symptoms yet. Even if anti-amyloid drugs can’t reverse symptoms, perhaps they can prevent full-blown Alzheimer’s. The prevailing view in the field, Selkoe says, is still that dealing with amyloid can treat the disease.