For more than 6 million people in the United States currently living with Alzheimer’s disease, finding new treatments that could halt its progression—or at least slow it down—is critical. And while many existing treatments can help manage Alzheimer’s symptoms, only recently have treatments begun to target the disease itself.
In 2023, lecanemab became the first drug for Alzheimer’s disease to be granted full approval by the U.S. Food and Drug Administration (FDA), based on its potential to slow the progression of cognitive decline. Made by Massachusetts-based biotech company Biogen and the Japanese pharmaceutical firm Eisai, lecanemab is currently sold under the name Leqembi.
Here’s what to know about lecanemab and the progress of treatments for Alzheimer’s disease.
What is lecanemab and how does it work?
Lecanemab belongs to a class of drugs called monoclonal antibodies. They can stimulate or change your immune response to clear cells that cause disease, or carry medicine to treat disease.
For those with Alzheimer’s, a protein called beta-amyloid collects between brain cells, forming sticky plaques that disrupt their function. Researchers have been studying whether monoclonal antibodies like lecanemab could prevent these plaques from forming or help the body clear them from the brain.
Lecanemab was evaluated in a phase 3, double-blind, randomized controlled trial, considered to be the gold standard of medical research. These trials assess adverse effects of a new drug and whether a treatment provides benefit.
Results published in 2022 in The New England Journal of Medicine suggested that lecanemab showed the potential to change the course of Alzheimer’s when started early in the course of the disease. After 18 months, compared to a placebo, the drug was linked to:
- Significant reductions in beta-amyloid plaques
- 27 percent slower rate of cognitive decline
- 31 percent lower risk of progressing to the next stage of Alzheimer’s
- 37 percent slower decline in activities of daily living
- Better maintenance of health-related quality of life
- Less wear and tear on caregivers
Lecanemab’s safety, effectiveness, and other concerns
Despite these promising results, lecanemab sparked some controversy due to its high cost, safety, and other concerns. Here’s what to know.
Adverse events
Adverse events among those who received lecanemab were common. Almost 30 percent of participants developed amyloid-related imaging abnormalities, known as ARIA, compared to about 11 percent who received placebo.
Sometimes, the plaques that have collected along blood vessels in the brain are pulled away by anti-amyloid antibody therapy, weakening those blood vessels, explains Kevin N. Hascup, PhD, assistant professor, Center for Alzheimer’s Research and Treatment at Southern Illinois University School of Medicine. This can result in a buildup of fluid, swelling, and microscopic bleeding in the brain—a complication called ARIA when it is detected on brain MRI.
ARIA most often develops at the beginning of treatment. Symptoms may include fatigue, headache, confusion, dizziness, falls, vision change, or nausea. But about 77 percent of people with ARIA and fluid accumulation in the brain do not have symptoms.
In most cases (88 percent), ARIA resolves on its own without long-term problems. Rarely, ARIA with microscopic bleeding may result in larger bleeding into the brain or stroke. People with underlying disease in the small blood vessels of the brain may be at increased risk for this more serious issue.
In the lecanemab trial, most ARIA were detected within the first three months of treatment. Almost 13 percent of people who received lecanemab developed ARIA with fluid accumulation, and just 2.8 percent of these people showed symptoms. ARIA with fluid accumulation resolved within four months in 81 percent of these people. About 17 percent of people who received lecanemab developed ARIA with microscopic bleeding and just 0.7 percent of these people showed symptoms.
Two people who received lecanemab died from large bleeding into the brain, compared to one person in the placebo group. In response, Biogen issued a statement, noting that in its assessment the deaths could not be attributed to lecanemab. These two people on lecanemab who died had other underlying health problems and were taking blood thinners, which could have contributed to their deaths, the company said. A third death was also reported but circumstances surrounding it were unclear.
“All the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall,” Eisai said in a 2022 statement.
Nevertheless, the safety results have fueled debate about whether modest improvements with lecanemab outweigh possible safety risks. “Considering lecanemab is for people in the early stages of dementia who are still high-functioning, these adverse events could worsen their quality of life,” Hascup says.
Effectiveness
Lecanemab did not actually cure Alzheimer’s—only slow its progression. And the difference between lecanemab and placebo on a standard scale that assesses cognitive symptoms in dementia suggests it may not necessarily make a very notable difference in people’s lives.
“What is important to keep in mind is that patients receiving lecanemab still experienced a decline in their memory, judgment, and quality of life—just to a lesser extent than those receiving placebo,” Hascup explains. “The modest improvement of someone on lecanemab may be overshadowed by the progressive nature of the disease when viewed through the lens of a caregiver or loved one.”
Accessibility
Another potential pitfall is that monoclonal antibodies are not always easy to administer. Most require traveling to a healthcare facility for an IV infusion and monitoring for potential reactions. And they can be costly and difficult to produce on a large scale. For the millions of people with Alzheimer’s, that raises questions of affordability and availability.
Timing
In addition, many people are diagnosed after Alzheimer’s has progressed and may not benefit from a drug that must be started early, before damage has been done. Better ways of identifying Alzheimer’s earlier may be needed to fully benefit from a drug like lecanemab.
Patients and their families may need to carefully weigh these risks and benefits with their healthcare providers (HCPs) before starting treatment, Hascup adds.
The debate over the amyloid hypothesis
Accumulation of beta-amyloid plaque is thought to be toxic to brain cells and lead to dementia. For two decades, this amyloid hypothesis has been the prevailing theory for the root cause of Alzheimer’s, according to Hascup. Many drug developers have gone this route, but this theory has yet to be proven and scientists remain divided. Some researchers question whether targeting amyloid is the best way to go.
One problem is that the field is littered with failed anti-amyloid drugs. In 2018, pharmaceutical company Pfizer gave up and stopped developing new drugs for Alzheimer’s altogether. In 2021, the FDA approved Biogen’s aducanumab, another anti-amyloid monoclonal, only for Biogen to discontinue the drug three years later. The company denied safety and effectiveness concerns, instead citing a new set of priorities in the company.
The string of failures has led some to argue that the amyloid hypothesis is wrong. Others believe the trials have design flaws because they include people who have already begun to show symptoms of Alzheimer’s. They liken Alzheimer’s to a slow burn, with the damage caused by amyloid starting many years before symptoms start. To reap the benefits, anti-amyloid therapy would ideally need to start as early as possible. Once symptoms start, the damage may be too extensive to halt or reverse the process.
Newer evidence that reducing amyloid with lecanemab may slow cognitive decline when treatment is started early enough could help settle this debate.
Richard J. Hodes, MD, the director of the NIH’s National Institute on Aging (NIA), issued a 2022 statement (before lecanemab’s FDA approval) acknowledging the disappointing results from clinical trials of anti-amyloid drugs. Dr. Hodes noted, however, that there is still a “strong scientific” rationale for continuing to explore anti-amyloid therapy, as well as other causes of Alzheimer’s. As a “complex disorder,” Alzheimer’s has many contributors, such as other proteins besides amyloid, inflammation, genetics, fat droplets, environmental factors like infections or pollutants, and changes to the blood vessels in the brain, he wrote.
Where does Alzheimer’s drug development stand now?
In 2024, the FDA approved a second treatment for delaying the progress of Alzheimer’s, a monoclonal antibody called donanemab. The drug was shown to significantly slow cognitive and functional decline in people with early symptomatic disease.
Meanwhile, pharmaceutical companies continue to test additional treatments. The NIA supports dozens of clinical trials each year. Some are exploring amyloid treatments, while others are exploring therapies designed to treat other possible causes of the disease.
For example, some trials are investigating drugs that could help clear tau protein, which accumulates and forms toxic tangles that are typically found in later stage Alzheimer’s disease patients, Hascup says. Some researchers think tau protein more strongly correlates with cognitive decline.
Other treatments undergoing clinical trials include those that reduce inflammation, improve brain metabolism, or restore chemical signaling. Hascup suggests, however, that multi-drug therapy may be the best bet in the long run. “Combination therapies based upon an individual’s amyloid or tau burden may provide even better therapeutic benefits,” he says.
Scientists are also working on an anti-amyloid vaccine. In 2021, researchers at Brigham and Women’s Hospital in Boston launched the first human trial of an Alzheimer’s nasal vaccine. It uses an innovative approach that stimulates immune cells in the brain to clear amyloid. It’s a spray that could be easy to administer, have fewer side effects, and could be more widely available for millions of people with Alzheimer's. Researchers think it may have the potential to prevent Alzheimer’s—not just treat the disease. Clinical trials for Protollin started in 2021 are ongoing.
The best prevention now, though, is to “do everything our mothers told us all those years ago,” Hascup says. “Eat a healthy diet, stay active, spend time with your friends, never stop learning, and get a good night’s sleep. The earlier in life you practice these habits the better chance you have at reducing your dementia risk.”
