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.
Framing the effects as a percentage also subtly suggests that patients who took the drug could still be doing 35 percent better than their peers years later, says Howard. But there’s little reason to think that should be the case. Within 18 months, both lecanemab and donanemab wiped most patients’ brains clear of excess amyloid beta, so taking the drugs for longer may not provide any additional benefit. And though the data is limited, there’s some preliminary evidence that patients don’t see any additional slowing of their cognitive decline after finishing their course of lecanemab, and from this point decline at the same rate as untreated patients—making any relative benefits of the drug smaller over time. Much more research is needed to understand the long-term effects of anti-amyloid drugs. But now that they are poised to obtain full FDA approval, Maria Glymour, a professor of epidemiology and biostatistics at the University of California, San Francisco, says she worries we may not ever have solid data. For the companies, she says, “there’s only downside” to interrogating the effects of their drugs further—so they might not do so.
It’s not just the benefits of these drugs that are uncertain. During the Phase III lecanemab and donanemab trials, a total of six patients may have died as a result of side effects. Amyloid-targeting antibodies frequently cause the brain to swell and bleed, and though most patients experience no symptoms, a few suffer serious consequences. Those risks weigh heavy on the minds of many clinicians. Lon Schneider, professor of psychiatry and the behavioral sciences at the University of Southern California, says he doesn’t think the benefits of anti-amyloid drugs will prove meaningful for most patients, but even so, he wouldn’t hesitate to recommend these drugs if they were safe. But the risks give him serious pause. “Even if it’s one in a thousand deaths, as with lecanemab, well, that’s a hundred deaths out of 100,000 people treated over the course of a year,” he says.
Rojas, who has administered both drugs to patients in the clinical trials, is more sanguine about their safety. Because the number of patients who died in the trials is so small, it’s impossible to say whether these drugs cause more deaths than expected, and he thinks the safety measures in place will likely protect patients from severe side effects. But those measures, like regular MRI scans to detect brain swelling, bring their own burdens. In the lecanemab trial, patients received an MRI every few months. Paired with biweekly infusions of the drug, that’s a substantial time cost for both patients and their families. For those who have to pay out of pocket for some or all of their health care, those appointments and tests may be unaffordable.
For patients who live near a major medical center and sit on comfortable nest eggs, those burdens might be manageable. But poor patients, rural patients, and those without family or social support might not be able to try the drugs, even if they want to. Others might not be eligible: In the US, Black and Hispanic patients are less likely to be diagnosed with Alzheimer’s in the early stage of the illness, when they would be candidates for anti-amyloid therapies.
If the drugs don’t have net benefits for patients, these disparities in access might not matter much in the long run. But a big focus on expensive drugs could make it more difficult to close more mundane gaps in dementia care that disproportionately affect marginalized Alzheimer’s patients. In the US, Medicare, the public health insurance program for older adults, doesn’t pay for the caregivers that many Alzheimer’s patients need, and communities tend to do a poor job of integrating those with cognitive impairments. These are fixable problems, but there’s scant energy to address them. “There’s something seductive about the idea of a pill or an infusion,” says Emily Largent, a bioethicist at the University of Pennsylvania. “It can definitely distract from the idea of interpersonal care.”
It’s been almost half a year since the FDA granted lecanemab accelerated approval, but so far, the drug has been nearly impossible to obtain. That seems likely to change soon: The FDA will meet to discuss a full approval for lecanemab next month. (Approval is still pending in Europe, and in the UK, it will also have to pass a cost-benefit test to be offered by the National Health Service.) Despite the risks and the difficulties involved in care, doctors do plan to offer lecanemab, and later donanemab, to patients who want them. “We’re not in the business of bashing hope,” Schneider says.
That said, doctors have an essential role to play in helping patients decide whether these drugs are right for them. Clinicians will have to navigate the limited available data to explain the outcomes that patients can expect. It will then be up to the patients to decide whether the possible benefits outweigh the costs—in time, money, and health.
People may be willing to take on grave risks for the chance of slowing their disease. For patients and families, an Alzheimer’s diagnosis conjures images of debility and incontinence, of deep emotional wounds unintentionally dealt to loved ones, of losing oneself inside one’s own mind—it’s been called a “death before death.” When faced with such a fate, a Hail Mary treatment might seem appealing. Howard says he’s had patients tell him that they would do anything to fight the disease, even if it kills them.
But candidates for anti-amyloid therapies are so mildly impaired that they can typically maintain their pre-Alzheimer’s lifestyles for a period, and may live for a decade or more with their disease. If they are elderly, there’s a good chance something else will kill them before Alzheimer’s does. The idea that a life with Alzheimer’s is of so little value as to make any treatment worthwhile may be widespread, but it erases the rich lives that people with memory impairment lead.
That only adds to the tragedy of each death caused by lecanemab and donanemab. “People with mild dementia, even moderate dementia, can live extremely fulfilling, happy lives,” Howard says. “Those people who died in those trials, those [were] people at the very, very early stages of their dementia. They still had years of reasonable life ahead of them.”
Updated 5-24-2022 12:00 pm ET: What may happen to patients after they finish their course of lecanemab was clarified.
