New Alzheimer’s Drugs Offer Subtle Benefits—With Real Risks

Nearly 30 years ago, when the first effective Alzheimer’s drugs were approved, optimism was in the air. True, the drugs didn’t slow the underlying disease, but they made a meaningful difference to symptoms. It seemed like disease-modifying drugs would be coming any day. “The story was, within a few years, we should have drugs that will actually interfere with disease processes,” says Rob Howard, a professor of old-age psychiatry at University College London. “We didn’t realize we were going to have to wait more than 20.”

Those treatments are finally here in the form of anti-amyloid therapies—antibodies designed to target a protein called amyloid beta that accumulates into plaques in the brains of people with Alzheimer’s disease. In June 2021, the US Food and Drug Administration (FDA) gave the antibody aducanumab a preliminary form of authorization called accelerated approval, though the decision was mired in controversy—many experts believed there was no reason to think the drug would help patients.

But with the next anti-amyloid drug, lecanemab, the story was clearer. It received accelerated approval in January of this year, after a Phase III trial showed that it modestly slowed cognitive decline, as measured by the Clinical Dementia Rating (CDR) scale, a tool for evaluating a person’s ability to accomplish the tasks of daily living. While all the patients studied saw their scores worsen over time, those on the drug saw theirs decline by 0.5 points less than patients receiving a placebo. And this May, Eli Lilly announced that its drug, donanemab, appears to slow decline a bit more—by about 0.7 points.

Predictably, there’s been a lot of excitement about potentially altering the course of Alzheimer’s. But rolling out these drugs will need careful consideration. The 0.5- and 0.7-point differences on the CDR are averages, so the real impact may vary substantially between patients, and a half-point difference might be too small to be meaningful. At the same time, the risks are substantial: Several patients may have died as a result of taking these drugs. Whether or not a drug with such modest benefits and weighty risks is “worth it” depends partly on how much one values a life lived with Alzheimer’s disease.

On the CDR, 0.5 points is the difference between “slight” and “moderate” impairment in a single area, like memory or community relationships. Those changes could be almost unobservable to an outsider: In one study of people with Alzheimer’s, doctors reliably saw a difference in patients only when their CDR score changed by one point or more. Patients, though, might notice things that escape doctors. Julio Rojas, an associate professor of neurology at the University of California, San Francisco, says that half a point of slowing could let someone drive independently for several additional months. “That’s meaningful,” he says.

The drugmakers, however, seem to have realized how unimpressive the CDR numbers sound. Eli Lilly’s press release doesn’t explicitly mention a 0.7-point benefit; instead, the company reports that donanemab slows cognitive decline by about 35 percent versus placebo. That 35 percent could mean anything out of context—if the patients on placebo had become radically sicker over the course of the study (which they didn’t), a 35 percent slowing could have enormous consequences. Left unquestioned, the number can suggest a bigger effect than what actually occurred.

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