Daily RC Article 391

Unraveling Alzheimer's: Hope and Doubts Surrounding the Amyloid Cascade Hypothesis

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Three decades ago, scientists thought they had cracked the medical mystery of what causes Alzheimer’s disease AD) with an idea known as the amyloid cascade hypothesis. It accused a protein called amyloid-beta of forming sticky, toxic plaques between neurons, killing them and triggering a series of events that made the brain waste away. The amyloid cascade hypothesis was simple and “seductively compelling,” said Scott Small, the director of the Alzheimer’s Disease Research Center at Columbia University. And the idea of aiming drugs at the amyloid plaques to stop or prevent the progression of the disease took the field by storm. Decades of work and billions of dollars went into funding clinical trials of dozens of drug compounds that targeted amyloid plaques. Yet, almost none of the trials showed meaningful benefits to patients with the disease. That is, until September 2022, when the pharmaceutical giants Biogen and Eisai announced that in a phase 3 clinical trial, patients taking the anti-amyloid drug lecanemab showed 27% less decline in their cognitive health than patients taking a placebo did.

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Because AD progresses over 25 years, the hope is that lecanemab, when given to people with early-stage Alzheimer’s disease, will slow that progression, said Paul Aisen, a professor of neurology at the Keck School of Medicine of the University of Southern California. By extending the milder stages of the disease, the drug could give people more years of independence and more time to manage their finances before being institutionalized. Some are less hopeful that the results will show any meaningful difference. “The clinically important difference is probably not there,” said Eric Larson, a professor of medicine at the University of Washington. On the scale the companies used to test the efficacy — calculated from interviews with the patient and their caregivers on their memory, judgment and other cognitive functions — their results were statistically significant but modest. And statistical significance, which means the results were likely not due to chance, does not always equate to clinical significance, Larson said. The difference in the rate of decline, for example, might be unnoticeable to caregivers.

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What’s more, reports of brain swelling in some participants and two deaths — which the companies deny are due to the drug — has some concerned about the safety of the drug. But Alzheimer’s medicine is a field more accustomed to disappointment than success, and even the announcement by Roche that a second much-awaited drug, gantenerumab, failed in phase 3 clinical trials didn’t diminish the excitement over the lecanemab news. Do these results mean the amyloid cascade hypothesis was right? Not necessarily. It does suggest to some researchers that with more coaxing, targeting amyloid could still lead to effective therapeutics. “I’m thrilled,” said Rudy Tanzi, an investigator at Massachusetts General Hospital. Lecanemab doesn’t offer a “stellar effect,” he acknowledged, but it’s a “proof of concept” that could potentially lead to more effective drugs or more effectiveness if taken earlier. Many researchers, however, aren’t convinced. To them, the small to non-existent effect sizes in these trials and earlier ones suggest that amyloid plaques are not the cause of the disease. Amyloid is “more the smoke, not the fire […] which continues to rage inside neurons,” said Small.