Side Effects of the New Alzheimer’s Drugs

New FDA-approved Alzheimer's drugs — Aduhelm, Leqembi, and Kisunla — have shown side effects, including brain bleeds and swelling. Are they worth the risk?

people on a bench wondering about new alzheimer's drugs
Emma Yasinski
Emma Yasinski Senior Reporter
Medically Reviewed By:Gina Jansheski, MD

On July 2, the U.S. Food and Drug Administration (FDA) approved Kisunla (donanemab-azbt), an intravenous drug designed to slow the progression of Alzheimer’s disease.1 About three weeks prior, on June 10, an FDA advisory committee met to discuss the drug and gave it a unanimous endorsement, but some experts remain skeptical that the new Alzheimer’s drug’s risks really outweigh its benefits.2

“I was not surprised that they approved the drug,” says Peter Whitehouse, MD, PhD, a professor of neurology at Case Western Reserve University. He was surprised, however, that the notes from the committee meeting seemed so enthusiastic. “They seemed to minimize the risks,” he adds.

Here’s what we know so far about this drug as well as two similar new Alzheimer’s medications (Aducanemab and Leqembi) approved over the past few years.

New Alzheimer’s Drugs and FDA Approval

For decades, the prevailing theory of Alzheimer’s disease has been the amyloid cascade hypothesis.3, 4 This is the belief that the disease is caused by an accumulation of clumps of a misfolded protein called beta-amyloid in the brain. The proteins stick together with immune cells and other material in the brain, creating blocks that interrupt and eventually kill communication between neurons. While amyloid plaques build up between cells, tangles of a protein called tau build up inside cells in the brain, leading to further damage.

Experts have begun to question parts of this theory in the past few years,5 as researchers discovered fraud in some of the field’s most influential studies.6 Still, the plaques and tangles have been associated with Alzheimer’s since Alois Alzheimer first described the disease in 1906.7 This is why many companies have continued to focus on developing drugs that clear beta-amyloid from the brain, in an effort to reduce Alzheimer’s symptoms.

In 2021, the FDA approved the first new drug for Alzheimer’s disease since 2003.8 The drug, Aduhelm (aducanumab), developed by Biogen, was the first drug on the market to help remove beta-amyloid from the brain, but Biogen withdrew it in 2024 amidst doubts about its efficacy.9 The company said it intended to focus on other Alzheimer’s drugs in its pipeline.10

In 2023, the agency approved another similar drug, Leqembi (lecanemab-irmb), manufactured by Eisai.11,12 This drug remains on the market. Kisunla, the drug approved July 2024, is the third intravenous infusion targeted beta-amyloid to reach the market. It is made by Eli Lilly.

All three drugs are monoclonal antibodies, proteins made in the lab that bind to specific molecules in the body. These monoclonal antibodies are designed to bind to beta-amyloid and remove it from the brain.

Do the New Alzheimer’s Drugs Work?

None of these drugs can stop or reverse Alzheimer’s disease, but they may slow its progression. The question that remains is whether they slow the process enough to make a meaningful difference for patients—and whether potential benefits are worth the risk.

Aduhelm

Because Alzheimer’s disease is a devastating condition that affects millions of people and there are no drugs on the market that can actually reverse its progression, the FDA approved Aduhelm based solely on how it impacted biomarkers, compounds found in the body that herald the presence of a disease. In this case, the biomarkers were beta-amyloid plaques.13, 14

The idea of the accelerated approval given to Adulhelm is that, because it was shown to reduce beta amyloid plaques, the drug must be causing metabolic changes that will likely lead to a clinical benefit.15 So the researchers don’t actually have to prove the drug directly causes that benefit. For example, a cancer drug could be approved based on the fact that tumors shrank in patients who took the drug, even if it’s unclear whether they actually lived longer than those whose tumors didn’t shrink.

The manufacturers of Aduhelm showed that the drug cleared beta-amyloid from the brain, but the results of two large clinical trials were mixed on whether or not this actually reduced symptoms of Alzheimer’s disease.16 After the drug’s accelerated approval, the company was required to continue clinical trials to confirm that getting beta-amyloid out of the brain actually did improve the quality of life of people with Alzheimer’s disease.

“When they [Biogen] submitted for accelerated approval, which only requires biomarkers for approval, we objected and led an effort to point out that this was not reasonable,” says Whitehouse, who calls himself “a recent critic of both the concepts of Alzheimer’s and the pressures to provide people anything at any cost.” 

The decision to approve Aduhelm was contentious, with three FDA advisory committee members resigning in protest. Aaron Kesselheim, MD, JD, a professor of medicine at Harvard Medical School who is also director of the Program On Regulation, Therapeutics, and Law at Brigham and Women’s Hospital, was one of the members that resigned. “I think there’s a real danger considering this to be a one-off event,” he told NPR, adding that the approval “now sets a precedent for the treatment of future [Alzheimer’s Disease] drugs, as well as drug approvals more broadly, and the amount of data they need.”17

He also spoke out on X, writing, “Accelerated Approval is not supposed to be the backup that you use when your clinical trial data are not good enough for regular approval.”18

Congress investigated, and found serious irregularities in the Aduhelm’s approval, including excessive collaboration between the drug’s manufacturer, Biogen, and the FDA. For example, the FDA helped Biogen develop a presentation about the drug to be given to the independent advisory committee. The FDA met with Biogen 55 times or more, and many of the meetings were not documented.

Aduhelm never escaped the controversy. Medicare refused to cover the drug outside of clinical trials, and many doctors were hesitant to prescribe it since the benefit for patients wasn’t yet proven.20 In 2024, Biogen decided to pull Aduhelm from the market.21

Leqembi

The approval of Leqembi (lecanemab-irmb) in 2022 was less contentious than that of Aduhelm, but still controversial. The drug was initially given accelerated approval, but in 2023, the FDA granted full approval based on clinical trial data suggesting that the drug slowed patients’ cognitive decline by 27% compared to the group taking placebo.22,23,24

This may sound like a lot, but some experts pointed out that this measure—a 27% slower decline—can make the benefit sound more powerful than it really is. It’s what’s called a relative value as opposed to an absolute value. In the study, researchers used a cognitive test on which patients can score 018. The lower the score, the better the patient’s current cognitive function. At the end of the trial, patients who took a placebo scored an average of 4.86 points, while patients who received Leqembi scored 4.41.

Representatives of PharmedOut, an organization that researches the influence of pharmaceutical marketing on the practice of medicine at Georgetown University, pointed out in a letter to the FDA that even though the difference between a score of 4.86 and 4.41 reached statistical significance, it was not considered clinically significant.25,26

“A minimal clinically meaningful difference is considered to be between 1.0 and 2.5 points, and the difference in this trial was 0.45. Moreover, there was no actual improvement, but only a slight difference in the extent of worsening, one that neither patients nor family would notice,” they wrote. Other experts have echoed the concerns.27

Kisunla

Kisunla (donanemab-azbt) was granted traditional approval as its effectiveness had been proven.28 In the clinical trial that Eli Lilly submitted to the FDA, patients with early Alzheimer’s disease who were given Kisunla did get better scores on cognitive assessments than their counterparts who had received placebos.29 Over the 18-month study period, Kisunla seemed to slow cognitive decline by about 4.4 to 7.5 months.

But Whitehouse emphasizes that it’s still not clear if these improvements actually translated to meaningful differences that patients’ friends and family would notice and that would improve their quality of life.

Additionally, the drug seemed to work best for people who had only a low or moderate amount of tau proteins in their brains at the start of the study. And there aren’t sufficient resources to offer patients a scan for tau to predict how well they might respond before prescribing Kisunla.

The FDA approved Kisunla for use in patients in the earlier stages of Alzheimer’s disease, regardless of how much tau protein they have.30

Side Effects of Monoclonal Antibodies for Alzheimer’s

Scientists are also debating the severity of the risks associated with Kisunla and Leqembi.

Brain bleeds and swelling

Bleeding and swelling of the brain are known side effects of all three drugs. These effects are known as amyloid-related imaging abnormalities (ARIA), which show up on brain scans.31

“Much of ARIA is asymptomatic, but of course, some become symptomatic to the point of seizures or strokes or death, and this requires frequent monitoring with MRI, which increases the burden to patients and families,” says Whitehouse.

Participants of the trials of each of the new Alzheimer’s drugs were different, so it’s not possible to make a direct comparison between the three drugs. However, all three saw a significant portion of patients experience ARIA. In the phase 3 clinical trials, 41.3% of patients using Aduhelm experienced ARIA, along with about 21.5% of the patients taking Leqembi and about 36.8% of people who received Kisunla.32, 33, 34

“It’s a significant issue,” says Whitehouse, especially, he adds, because the trial participants are carefully selected, and the people who might receive the drug once it’s on the market may have a variety of other conditions or be taking other medications that raise their risk. “They may be on anticoagulants, or they may have blood vessel disease that would, for example, increase the risk of hemorrhage.”

Some experts point out that, while many cases of ARIA associated with the new Alzheimer’s drugs appear to be asymptomatic and resolve on their own, some have devastating effects. In January of 2023, researchers reported that ARIA symptoms can present like a stroke, which is especially problematic because the condition can be worsened by stroke treatment.35 One woman in the Leqembi trial died after emergency room doctors administered a clot-busting drug to help ease the damage of a stroke they suspected she was experiencing. The treatment caused hemorrhaging throughout her brain.

1–2% of patients treated with these drugs experience serious symptoms due to ARIA, including headache, seizures, delirium, impaired speech, problems with vision, and muscle weakness. Alzheimer’s clinical trials typically run for 18 months. What happens to the memory and functional abilities of these patients after these trials end? Madhav Thambisetty, MD, wrote in STAT News.36 The adjunct professor of Neurology at the Johns Hopkins University School of Medicine served as a member of the FDA’s Peripheral and Central Nervous System (PCNS) advisory committee that evaluated a biologics license application for aducanumab in November 2020.

Deaths

Four patients died while taking Aduhelm due to problems that may have been treatment-related, and three died during the Leqembi trials.37,38 Manufacturers have not always been forthcoming about the deaths—some of which occurred during clinical trials and others after the drugs hit the market—with some details revealed during journalistic investigations.39

During the Kisunla trial, the scientists reported that three people (out of 860) who received the drug died as a result of treatment-related effects.29

One of the potential benefits of Kisunla is that it doesn’t necessarily need to be taken indefinitely. In the trial, when participants’ amyloid plaque levels dropped below a certain threshold, researchers stopped giving them the drug. The company stated that 17% of people were able to stop treatment after six months, 47% at 12 months and 69% at 18 months. It will take several more years of research to determine if and when patients would need to restart taking the medication, though the company currently estimates that patients’ amyloid levels will remain below the treatment threshold for about four years.40

Do the New Alzheimer’s Drugs Shrink the Brain?

In addition to ARIA, there’s another potential safety issue that hasn’t gained as much attention. “All of the monoclonal antibodies that attack amyloid so far that have been studied cause brain shrinkage,” says Whitehouse.41 “Of course, shrinkage of the brain is associated with the disease process itself, so we really need to understand that aspect. Whether it’s because of damaged neurons or whether it’s changes in fluids in the brain … unfortunately, it’s just often ignored.”

There are still additional safety questions that need to be answered. For example, most clinical trial participants for these drugs were white, meaning the results may not extend to people of color, which is particularly important considering Black and Hispanic individuals develop Alzheimer’s at a rate of up to twice that of white people.42,43

Researchers also want to know more about how the new Alzheimer’s drugs interact with other treatments, such as blood thinners, given that many people with Alzheimer’s are taking several other prescribed medications.

Unfortunately, regardless of the risk, no available approved drugs for the treatment of Alzheimer’s can reverse or cure the disease. Many factors contribute to your risk of developing the disease; some you can change, and some you can’t (such as genetics). To learn more about lifestyle changes you can make to reduce your risk or ease symptoms, check out MedShadow’s Prevent Alzheimer’s: Lifestyle Modifications You Can Make Today and Can Art Therapy Slow Cognitive Decline?