"Yet another new drug can temporarily hold off the mental decline caused by Alzheimer’s disease, scientists say.
The drug, called donanemab, slowed cognitive decline by about 35 percent over the course of a year and a half, according to data presented July 17 at the Alzheimer’s Association International Conference in Amsterdam and published the same day in JAMA.
The finding comes just weeks after the U.S. Food and Drug Administration gave full approval to another drug, called lecanemab (brand name Leqembi), that can also slow the disease’s progression. Another similar drug, known as aducanumab (Aduhelm), received accelerated approval in 2021, though access to it is still very limited.
These drugs target amyloid, a sticky protein that piles up in the brains of people with Alzheimer’s. The arrival of this new treatment approach marks a turning point in what has been a long, hard slog to come up with ways to slow the disease.
“I think this truly represents a sea change,” says neurologist Jeffrey Cummings of the University of Nevada, Las Vegas. “It’s one of the rare times where it’s OK to use the word ‘breakthrough.’”
The developments may bring a bit of hope to the 6.7 million people ages 65 and older in the United States who have Alzheimer’s. Even so, lots of questions remain, including who should get the drugs, how well they work and how to weigh the possible benefits against the risks, which can be significant.
One thing is already clear: The drugs aren’t for everyone. They come with risks and require close monitoring. And, even if a person is a good candidate medically, high costs, limited availability and time-intensive dosing schedules could prevent the drugs’ widespread use.
Here’s what to know about these new medications.
How do these Alzheimer’s drugs work?
The “mab” that ends their unwieldly names — donanemab, lecanemab and aducanumab — is a clue to their job: All three of these drugs are monoclonal antibodies.
These custom-designed antibodies take inspiration from the antibodies that the body makes to detect harmful substances, a key part of the immune system. In the brain, the lab-made antibodies attach to specific parts of amyloid plaques, a hallmark of Alzheimer’s. Once the antibodies attach to amyloid, they call in other immune cells to come take out the trash.
This cleanup job brings mental benefits, recent clinical trials suggest. And that finding supports the idea that amyloid plaques are a key part of Alzheimer’s disease, a long-standing idea called the “amyloid hypothesis” (SN: 2/25/11).
Failed clinical trials had led some researchers to abandon that idea. “People were about ready to give up on amyloid altogether,” says neurologist and neuroscientist Erik Musiek of Washington University in St. Louis. “I don’t think a lot of people felt like removing the plaques was that big of a deal.” But this new class of drugs suggests that the plaques aren’t innocent bystanders.
Instead, plaques do indeed seem to harm brain function, and getting rid of them helps, Musiek says. “It seems to suggest that getting those plaques out of there is important.”
How well do these Alzheimer’s drugs work?
None of these drugs stop the disease. But they can buy some time, the data suggest.
On average, the 588 people who received donanemab in the recent clinical, for instance, stayed sharper for a bit over four months longer than the 594 people who received a placebo. Using a different scale to measure symptoms gave an estimate of seven and a half months of extra time due to the drug, made by the pharmaceutical company Eli Lilly, based in Indianapolis.
Results from studies of aducanumab are more mixed, generating lots of debate about whether the drug, made by Biogen Inc., based in Cambridge, Mass., is effective (SN: 6/7/21).
For lecanemab, a drug made by Eisai Co., based in Tokyo, and Biogen, people who got the drug spent about five months longer in a milder stage of the disease before developing more severe symptoms than people who got a placebo — about a 30 percent delay over the course of the 18-month study. That may not sound like a lot, and for some people, it might not be worth the drug’s risks. But Aimee Pierce, a geriatric neurologist at Oregon Health & Science University in Portland, says that for some people, that delay could be especially meaningful.
“Some of my patients are writing memoirs or writing books or still struggling through their last year of teaching.” In those circumstances, a five-month reprieve before progressing to more confusion is significant, she says.
So far, the studies have not been representative of the broader population, enrolling very few people who are Black or Hispanic, for instance. That leaves a lot to learn.
Who can get Alzheimer’s drugs?
So far, the drugs are for people who are showing mild signs of Alzheimer’s disease. Scientists don’t expect the drugs to help once Alzheimer’s has progressed to more intense stages.
To be treated with the drugs, a person should have amyloid plaques in their brain. That’s confirmed with either a brain scan or a cerebrospinal fluid test that can detect amyloid. New blood tests for amyloid buildup — a less-invasive option — are also being studied (SN: 2/1/18). The recent study of donanemab also required people to have excess tau in their brains, another sign of Alzheimer’s, to qualify for the trial.
Autoimmune disorders, medical implants that preclude MRI scans that monitor brain reactions and other health issues may also stop someone from being a candidate for the drugs. People who carry APOE4, a version of a gene that ups a person’s risk of Alzheimer’s, seem to be at higher risk of harmful side effects from the drugs too.
How are the Alzheimer’s drugs delivered?
The drugs are intravenous infusions that are given in medical centers where health care workers monitor reactions.
Aducanumab and donanemab are monthly infusions. But it’s possible that donanemab may be stopped once plaques are cleared away. In the clinical trial presented July 17, some participants were switched to a placebo once their plaques were gone. Still, the benefits lasted throughout the trial.
Lecanemab infusions happen every other week. That intense dosing schedule can be tough for patients, says Pierce, who was involved in one of the lecanemab clinical trials. And there’s no good cutoff for when to end the treatment. “As of now, it’s out there and people don’t have a stopping point,” she says.
What are the risks of taking Alzheimer’s drugs?
Brain swelling and bleeding are two of the risks. In the recent trial of donanemab, three people died as a consequence of the treatment. People on the drugs ought to be monitored with brain scans that can detect possibly dangerous changes, researchers say. Those scans can identify the worrisome condition ARIA, or amyloid-related imaging abnormalities.
Overall, about a quarter of people in the clinical trials who received the drug developed the condition. In a trial of nearly 1,800 people, for instance, about 21 percent of people who received lecanemab had ARIA, while about 9 percent of people who got a placebo did. Most of those cases came without symptoms, which can include headache, nausea, dizziness and seizures.
Scientists suspect that ARIA stems from the antibodies working well. Amyloid can be in the walls of blood vessels. Removing the amyloid may make the blood vessels less stable and more prone to break.
These drugs can also lead to infusion reactions such as changes in blood pressure, fevers and chills. Those are often temporary and manageable, Cummings says, nor are they specific to these treatments. “This is not unique at all to Alzheimer’s drugs.”
Weighing the risks and the potential benefits of taking the medications is a personal call. An 80-year-old with a list of medical problems who is generally content might have a very different calculation from a 62-year-old CEO of a company with a kid in college, Musiek says. If you are that younger person, “your appetite for risk is probably much higher,” he says.
Researchers hope that this spate of drugs may serve as a stop-off on the way to even better ones that are more effective, less risky and easier to administer.
“Hopefully once we can optimize [these drugs] and help whoever we can help, it will pave the way for the next set of drugs that will come out,” Musiek says. “And then maybe things will get better and better.”"
New Alzheimer’s drugs are coming. Here's what you need to know (sciencenews.org)