The US approved an Alzheimer’s drug. Seven patients subsequently died.

“They should have known not to take her with her genetic status,” Porter said in an interview. “It’s almost like they put her in front of a firing squad.”

The hospital declined to comment on Aaron’s case, citing confidentiality laws, but said all patients with genetic risk factors are warned of these risks.

Aaron is one of at least seven people who have died in the US from symptoms linked to the drug Leqembi over the past two years, according to a Bloomberg review of federal records obtained through the Freedom of Information Act. Three others have suffered lasting disabilities, according to these FDA reports. Each case Bloomberg counted was based on detailed adverse event reports that specifically mentioned brain swelling or bleeding, possible side effects of Leqembi that were controversial at the time of the drug’s approval.

This is the exact outcome governments in other parts of the world have been trying to prevent. Leqembi competes with a similar drug from Eli Lilly & Co. called Kisunla, which can cause similar side effects.

On Friday, European regulators rejected Lilly’s drug, citing the risk of potentially fatal brain bleeding. That follows Australia’s drug regulators deciding against making Leqembi available in October, saying its benefits didn’t outweigh the brain bleeding and swelling risks. Eisai appealed and lost on March 3. In Europe, regulators first rejected Eisai’s drug for similar reasons in July. After an appeal, regulators reversed that decision and recommended allowing it onto the market — just not for people with Aaron’s genetic makeup.

Eisai shares dropped 3.6 percent in Tokyo on Monday. Lilly shares fell 3.9 percent at 9:42 a.m. Monday on New York.

The FDA took a different approach, making the drug broadly available for patients with early Alzheimer’s and leaving it up to doctors and medical systems to decide who should get it, with few restrictions on its use. Prescribing standards vary sharply from hospital to hospital, a Bloomberg review found, with some willing to treat patients at far higher risk of side effects.

Leqembi — sold through a partnership between Eisai and Cambridge-based Biogen Inc. — is one of the first medications approved that promises to slow the speed at which Alzheimer’s erases a person’s memory. Nearly 7 million Americans have Alzheimer’s, a disease that has had no real treatments to slow its course. Studies of Leqembi didn’t show any improvement in patients, but did lead to a 27 percent slowing in their rate of decline.

Even a modest reduction in the progression of Alzheimer’s offers long-awaited hope for patients and families. The medical system is divided — some doctors think patients who want the drug should be allowed to try it yet others think the side effects are too risky and that Leqembi should be kept under tighter control.

“These deaths are incredibly important,” said Caleb Alexander, a Johns Hopkins University epidemiologist, adding they “need to be examined carefully.” He predicts that risks of serious side effects from Leqembi are “all but certain” to increase as the drug moves from the carefully curated population that was studied in clinical trials into the real world.

Aaron was one of roughly 15 percent of Alzheimer’s patients with two copies of a gene variant called APOE4, which put them at higher risk for developing brain swelling associated with the drug, according to clinical trials. In Eisai’s main approval trial, almost 33 percent of people with two copies of the gene who got the drug experienced brain swelling compared to just 5 percent of people with no copies. While most cases are asymptomatic, some can cause headaches, confusion and even seizures.

In a statement, Eisai acknowledged “rare post-marketing reports of fatal events and disability” among patients on Leqembi. But it noted that the federal database contains “incomplete, inaccurate, untimely and/or unverified information” that does not prove cause and effect. Outside of a clinical trial, “it is not possible to provide a precise number of safety reports,” it said. It also notes that brain hemorrhage deaths can happen in the general population.

So far, roughly 13,500 US patients have used Leqembi, which costs about $26,500 a year.

The FDA, in approving the drug, said brain swelling and bleeding “usually resolves over time” but “infrequently” can be life-threatening. It recommends that if a person has symptoms that indicate this side effect, “clinical evaluation should be performed, including MRI.”

The FDA said it's monitoring the deaths of patients treated with the new Alzheimer's drugs and that it included the “strongest warning possible” on the label to convey that certain patients have increased risk of brain bleeding and swelling. But the agency approved Leqembi broadly because it “recognizes the importance of allowing patients to make informed decisions in discussion with their health care provider, evaluating both possible benefits and risks,” a spokesperson said.

Realizing that community doctors needed more guidance about how to use the drug safely, a group of top academic doctors came out with their own, stricter rules in 2023, excluding patients with certain preexisting signs of brain bleeding and those on anticoagulants. Some Alzheimer’s patients who died had “clear warning signs” that weren’t heeded, said Stephen Salloway, a neurologist at Brown University who worked on the recommendations. “Not everyone is following the guidelines.”

One 69-year-old woman was told she was at risk of brain bleeding from Leqembi but that she was still a candidate for treatment, according to an adverse event report. Two days after her fourth infusion in July, she developed stroke-like symptoms. There was no stroke. It turned out to be “brain swelling due to the Leqembi,” according to the report. She died a week later.

Another 84-year-old became disoriented less than two weeks after a third dose in December 2023. An MRI found more than 10 brain bleeds and a 4-inch-wide area of brain swelling. The patient had a seizure “considered related to Leqembi” that led to “generalized brain dysfunction,” according to reports on the case. The patient was dead about two months later.

Eisai says it has developed a lay-language brochure about brain swelling and bleeding for patients and maintains an educational website for doctors and health professionals. It says more restrictions on the drug are not necessary given the rarity of the severe side effects.

The restrictions that do exist are significantly limiting the use of the drugs, as patients must undergo regular MRI monitoring, said Donna Wilcock, a neurology professor at Indiana University who is studying why the new Alzheimer’s drugs are causing the brain side effects. That makes the therapy less accessible to those outside major cities, she said. “It’s holding us back in our ability to treat the most Alzheimer’s patients that we can.”

Indiana University's medical system has adopted a rigorous screening protocol, including MRIs to detect past brain bleeds and genetic testing. The university also won't treat patients if they have signs of having suffered small strokes, damage to small brain vessels or are taking anti-coagulants for heart disorders.

Wilcock said her center does not automatically disqualify people with two APOE4 genes from getting the drug, because most of those patients don’t get symptoms from brain swelling. People “should be able to make an informed decision based on the data we have, especially since right now there is no other treatment to be offered,” she said.

When people suffer bleeding or swelling in the brain, the symptoms can mimic a stroke. ER doctors who see these patients might end up using what are known as “clot-busting drugs,” a standard stroke treatment, that can worsen brain bleeding and ultimately even be deadly.

During an extension phase of Eisai’s main approval trial, a 65-year-old woman developed stroke-like symptoms days after her third dose of the drug and was given clot busters, causing bleeding in at least seven areas of her brain, according to reports by Northwestern University researchers. She died.

Matthew Schrag is a neurologist at Vanderbilt University Medical Center and has studied the adverse effects of drugs that lower amyloid, a protein that builds up in the brains of people with Alzheimer’s. “Most of the cases that I have personal knowledge about came to the ER at some level or other as the mimic of a stroke,” Schrag said.

More broadly, Schrag says the widespread rollout of Leqembi and similar drugs raises hard-to-answer questions. While the risks of severe side effects are small, the long-term benefits remain murky, he says, as the key studies are based on 18 months of study in a disease that unfolds over many years. For many patients, “we don’t have clear evidence that the benefits outweigh the risks,” he said.

Lilly’s rival drug, Kisunla, was approved in the US and hit the market last summer — a year and a half after Leqembi. It works similarly, by attaching to toxic clumps of amyloid and stimulating their removal from the brain. It also may cause brain swelling and bleeding, according to the FDA’s warning on Kisunla’s label. Prior to the drug’s approval, Lilly reported several fatalities linked to brain swelling in various clinical trials.

One death of a Kisunla patient with brain swelling is listed in the federal database since the drug was approved. A Lilly spokesperson said that just because the incident is in the database does not mean the drug was the cause of death.

Lilly calls patient safety its “top priority” and says it’s investing in research to better understand the brain bleeding risks. The company also has developed support programs to help doctors and patients.

In October, Lilly reported results from a trial that showed giving a lower dose for the first infusion could reduce the rate of brain swelling, and regulators are urgently reviewing the data for a potential label update.

“Like all drugs, there is a risk here,” said Daniel Skovronsky, Lilly’s chief scientist, in a January interview. “The US has decided to leave more autonomy” to patients who feel the benefits are worth it, he said when asked if he thought there should be more restrictions on these types of drugs.

People with two copies of the APOE4 gene can’t get these drugs everywhere in the US. Johns Hopkins School of Medicine doesn’t recommend the treatments to these patients given the risks. The US Veterans Health Administration doesn’t either.

At the Mayo Clinic in Rochester, doctors last year developed a “higher-risk protocol” for people with two copies of APOE4 that adds additional monitoring and reduces the strength of early doses of the drug to minimize risks, according to neurologist David Knopman.

Many big hospitals do treat patients with two APOE4 genes though, including Columbia University Irving Medical Center, where Susan Aaron was treated. Aaron had started leaving Post-It notes around her apartment because she couldn't remember basic things, like when she had an appointment.

She wanted to slow the disease so she could “remain competent, still drive my car safely and take care of myself,” she wrote in a December 2023 email to her nurse practitioner at Columbia that Bloomberg reviewed.

“If you think I’ll start sliding downhill any time within the next five years, then maybe we should discuss Leqembi at my next visit in March,” she said in the email.

The nurse practitioner suggested that she undergo genetic testing, adding that it helps monitor patients on the drug.

“This will hold no weight on moving forward with Leqembi,” the nurse added.

That testing found that Aaron carried two copies of APOE4. She was given her first dose of the drug on May 29 last year.

A spokesperson for the Columbia medical center declined to comment on Aaron’s case but said it informs “all patients” with the APOE4 gene that they have a higher risk of life-threatening complications from Leqembi.

Aaron became increasingly confused after her third infusion. A week later, Valerie Porter found her collapsed at home. She died six days before her 75th birthday.

“The way she died was so horrific, I wouldn’t wish this on my worst enemy,” Porter said. “She had some decent years left and they took that away from her and me.”METHODOLOGY: Bloomberg’s count of deaths and disability cases is based on detailed adverse event case reports to the Food and Drug Administration obtained through the Freedom of Information Act and includes cases that specifically mention brain bleeding, brain swelling, or brain hemorrhage, while excluding potential duplicate reports. The count does not include previously disclosed deaths in the extension phase of Leqembi’s clinical trial.

With assistance from Aisha Ziaullah.