Since the approval of new Alzheimer’s drugs in recent years, there has been a lingering question: While data indicated that they could modestly slow cognitive decline for some patients, would that effect be meaningful or too slight to make difference?
A new review of research spanning a decade, published on Wednesday, concluded that the clinical benefit of these and similar drugs is negligible. But the way the review was conducted spurred heated criticism from many Alzheimer’s experts, including some who had been skeptical of some of them.
The review, published by Cochrane, an international network of health researchers, evaluated studies that were conducted on seven monoclonal antibody drugs developed over the last two decades to target amyloids, proteins that form plaques in the brains of people who have Alzheimer’s disease.
Some Alzheimer’s experts said the conclusions were meaningless because the review swept under one umbrella drugs that had shown very dissimilar results and worked differently. The experts noted that data from the two most recent drugs studied — Leqembi and Kisunla — showed they could slow cognitive decline, which led to approval from the Food and Drug Administration and made them the only anti-amyloid drugs available to patients.
But a vast majority of the studies analyzed in the review involved four earlier drugs that had failed clinical trials or were never approved and a fifth drug that was pulled from the market.
“The problem with the review is the mix of ingredients,” said Dr. Jason Karlawish, a director of the Penn Memory Center at the University of Pennsylvania, who has been skeptical or cautious toward some of the drugs over the years. “They took some of the rotten ingredients and mixed it in with the fresh food, and the result is a stinky stew.”
The review looked at 17 studies conducted from 2014 to 2024 and funded by the drug companies. All were randomized clinical trials in which patients who received one of the drugs were compared with those receiving placebos. The trials involved many countries and about 20,000 patients, who were 70 to 74 years old on average and were in the early stages of the disease, either with mild dementia or a pre-dementia condition called mild cognitive impairment.
The analysis evaluated results from 18 months of treatment, a length of time that its authors said was too short to assess the drugs’ long-term impact.
Receiving anti-amyloid drugs for 18 months “may make little to no difference to how bad people’s dementia symptoms are” and would “probably make little to no difference in the decline in memory and thinking ability or the ability to manage everyday activities,” the researchers wrote. But they also found that such treatment “may result in a small improvement in more complex everyday tasks, such as shopping, managing finances, taking medication and using transportation.”
The review also said the drugs probably pose an increased risk of brain swelling or bleeding — widely known side effects of the treatments. It added that those brain side effects appeared to cause no symptoms for most patients. The drugs “do not increase other serious unwanted effects” and “do not increase deaths,” the review concluded.
An author of the review, Dr. Francesco Nonino, a neurologist and epidemiologist at the IRCCS Institute of Neurological Sciences of Bologna, Italy, said in a news briefing that the analysis concluded that anti-amyloid drugs “have no clinically meaningful effect on cognitive decline or dementia severity.”
Some experts praised the review. In a statement, Robert Howard, a professor of old age psychiatry at University College London, called it “well conducted.” The data on the most recent anti-amyloid drugs showed “very small benefits of treatment,” he said.
“While these benefits may have achieved statistical significance within clinical trials where very large numbers of participants allowed the detection of tiny differences,” he said, “they did not achieve accepted levels of clinical efficacy or what would be appreciable in an individual patient.”
But Susan Kohlhaas, the executive director of research at Alzheimer’s Research UK, a nonprofit, noted in a statement that the drugs in the review do not all target the same type of amyloid or have the same biological impact on the brain.
“This study is attempting to paint an entire class of drugs with the same brush even though we know different anti-amyloid treatments can act in different ways,” she said.
Dr. Karlawish said the earlier years of anti-amyloid research focused on discovering “what kind of anti-amyloid molecule targeting what aspect of amyloid and what dosage and what frequency.” He added the review included many studies that “were experiments that deliberately intended to figure out the answers to those questions.”
“Some colleagues wonder if we went back to some of these earlier drugs, knowing what we know now, maybe they might actually be effective,” he said.
Four of the drugs studied — bapineuzumab, crenezumab, gantenerumab and solanezumab — were never considered for F.D.A. approval. A fifth, aducanumab, was given conditional approval in 2021 and marketed as Aduhelm. But, it was ultimately discontinued by its manufacturer, Biogen, because of weak evidence of effectiveness, risks of brain swelling and bleeding, and controversy over how it was approved that prompted a congressional inquiry.
The other two drugs are currently being used by patients: lecanemab, approved in 2023 and marketed as Leqembi by Eisai, the drug’s developer, and Biogen; and donanemab, approved in 2024, made by Eli Lilly and marketed as Kisunla. The review evaluated only one clinical trial for each of those drugs, the same clinical trials evaluated by the F.D.A. when it approved them. Those trials found that the drugs could slow cognitive decline by several months over a period of 18 months, but it was unclear from those results whether patients would perceive that benefit.
Determining what is a noticeable effect in Alzheimer’s can be difficult, many experts say, because the mix of symptoms and pace of decline can vary by patient. If the progression of the disease in a mildly impaired patient is slowed by several months, the decline is nonetheless continuing, and it’s unclear whether the patient or family members perceive that the person’s memory is fading more gradually than it might have without treatment.
Another author of the review, Edo Richard, a professor of neurology at Radboud University in the Netherlands, said “benefit” should translate into something patients or caregivers “can notice.” According to the metrics his team used to measure meaningful impact, he said, the drugs’ benefit was “far below the minimal effect that’s needed to be noticeable at all for patients and caregivers.”
But Dr. Kohlhaas said whether medications were “clinically meaningful” could be in the eye of the beholder, “and current trial measures don’t always reflect what matters most to people with dementia.”
Dr. Richard defended the decision to include both failed and approved drugs that had different approaches to amyloid, saying “these drugs all target the same protein.” Dr. Nonino said the team’s separate analyses of lecanemab and donanemab yielded conclusions that “are perfectly in line with the pooled estimate” for all the drugs.
In a statement, Eisai called the review “scientifically deeply flawed” and said “extensive long-term clinical data out to four years and real-world experience with tens of thousands of patients globally show that patients who receive lecanemab continue to benefit from treatment.”
Eli Lilly said that “combining data on unsuccessful molecules with approved medicines artificially dilutes the observed benefit and produces class-level conclusions that do not reflect the evidence for any individual approved therapy.”
The review authors noted that there would be more data on the two drugs now on the market, plus results from anti-amyloid drugs being tested at even earlier stages of the disease, to see if they can prevent people from developing symptoms. The authors said they did not expect future data to change their conclusions.
They called for more focus on other targets for treatments, something many researchers were already doing. That suggestion was more widely embraced by experts.
“Anti-amyloid treatments will not be the whole answer to curing Alzheimer’s, and research is already moving toward a wider range of biological targets,” Dr. Kohlhaas said. “But it’s not accurate to dismiss their impact as ‘trivial,’ especially when the analysis has clear constraints that limit what it can tell us.”
Pam Belluck is a health and science reporter for The Times, covering a range of subjects, including reproductive health, long Covid, brain science, neurological disorders, mental health and genetics.
The post Analysis of Alzheimer’s Drugs Stirs Debate About Their Effectiveness appeared first on New York Times.
