For the first time, scientists say, they have evidence that using a biologic drug to remove sticky beta amyloid plaques from the brains of people destined to develop Alzheimer’s dementia can delay the disease.
The researchers have been testing amyloid-removing therapies in a group of people who have rare genetic mutations that make it almost certain they’ll develop Alzheimer’s.
The study – which is small, including just a few dozen participants – is a follow-up to a randomized-controlled trial that found no significant benefits for people who were taking one of two amyloid-lowering therapies, compared with a placebo. The extension of the study doesn’t have a placebo control group and may be subject to important biases, so outside experts say the results, though striking, should be interpreted with caution.
It’s part of a research effort called Dominantly Inherited Alzheimer’s Network, or DIAN. The study participants like to go by a different name, though.
“We like to call ourselves the X-Men because we are mutants, trying to save the world from Alzheimer’s disease,” said Marty Reiswig of Denver, who has been participating in the trial since 2010.
The new study, published Wednesday in the journal Lancet Neurology, found that the risk of symptoms was cut in half for a small subset of 22 patients who had not shown any problems with memory or thinking and had been taking an amyloid-lowering drug called gantenerumab for an average of eight years. The results achieved statistical significance in one part of the analysis but not in others, perplexing outside experts, who struggled to make sense of the complex findings.
“While this study does not conclusively prove that Alzheimer’s disease onset can be delayed and uses a drug that will not likely be available, the results are scientifically promising,” said Dr. Tara Spires-Jones, director of the Centre for Discovery Brain Sciences at the University of Edinburgh, in a statement to the media. She was not involved in the research.
The study authors believe that if people are started on therapy early enough and stay on it for enough time, it could forestall the development of the disease — perhaps for years.
It’s “the first data to suggest that there’s a possibility of a significant delay in the onset of progression to symptoms,” said study author Dr. Eric McDade, a professor of neurology at Washington University in St. Louis.
McDade said this study has the longest-running data for any patients who started amyloid-lowering biologics while they were still free of symptoms.
“We think that there’s a delay in the initial onset, maybe by years, and then within those individuals that have some mild symptoms, even the rate of progression was cut by about half,” he said.
The achievement of this long-hoped-for result comes with optimism but also panic, however.
The research team says the meetings to review their National Institutes of Health grant funding have been canceled twice. Their grant has to be reviewed before they can be referred to what’s known as a council meeting, where funding decisions are made. If their grant misses a council meeting in May, the money for the study, which has been going since 2008, could run out.
“It ends up becoming a really difficult position we’re in and that the participants are in,” McDade said.
Patients could lose access to the study drugs, especially if they’re in countries where the medications haven’t been approved. If people can’t stay on the drugs, researchers may never find out how durable the benefit may be or be able to answer critical questions like for whom the medications work best.
Keeping that group that has been on the amyloid drugs the longest is “absolutely critical,” McDade said.
Long-running studies begin to bear fruit
In the 1980s, researchers studying the autopsied brains of people with Alzheimer’s discovered that they were clogged with sticky plaques made from beta amyloid proteins and toxic tangles made of a protein called tau. They theorized that removing these proteins from the brain might delay or even reverse the disease, and they began to hunt for therapies that could do that.
For decades, scientists have been testing a range of biologic medications that recognize and remove beta amyloid proteins, with mostly lackluster results.
In late-stage clinical trials involving more than 1,800 people with early Alzheimer’s disease, one of these drugs, gantenerumab, slowed the progression of symptoms compared with a placebo, but it wasn’t a big enough benefit to pass a test of statistical significance, meaning the result could have been due to chance alone. It was considered a failed drug.
Meanwhile, two similar drugs — lecanemab, or Leqembi, and donanemab, or Kisunla — did meet the US Food and Drug Administration’s bar and were approved to treat people with Alzheimer’s who have mild symptoms.
Both therapies are expensive, may cause brain swelling and, in clinical trials, delayed the progression of symptoms by months compared with placebos. The modest benefits mean some doctors and patients to shy away from using them.
Researchers testing gantenerumab in people with gene mutations that set them up for Alzheimer’s in the DIAN got permission from the FDA to continue using the drug for as long as possible. When they couldn’t keep the participants on gantenerumab any longer, they switched them to its sister drug lecanemab.
Sue, a study participant in Texas, has been in the gantenerumab arm of the trial since 2012. She joined the study shortly after she found out that she and three of her five siblings had a gene mutation that made it almost certain they would develop early-onset Alzheimer’s disease.
Of six children in her family, two brothers and two sisters have the mutation. One brother was tested but doesn’t have it, and another brother doesn’t want to be tested but remains free of symptoms. Two of her brothers and a sister developed symptoms around age 57. Sue, who at 61 is the youngest of her siblings, has not.
“I’m fine. I’m totally fine,” said Sue, who asked to be be identified only by her first name to protect family members who may also have the mutation.
Her brothers, who were also in the trial but began taking the medication after they had developed symptoms, didn’t benefit as much.
When she started the study 13 years ago, she hoped she would contribute to scientific understanding of the disease. She has had 40 MRIs, 30 PET scans and more than a dozen lumbar punctures to collect her spinal fluid.
Tests show that her brain and her thinking are normal. She gets “queen bee,” the top daily ranking, on the New York Times Spelling Bee game every day.
“I still feel like, fundamentally, I’m doing it to help the science, but at this point, it’s helping me,” she said. “I truly believe that.”
Sue believes the drugs have held off the disease for about four years for her. When the disease runs in families this way, she believes, there’s a pretty clear age when people start to decline, and she thinks the medication has pushed that back.
After watching her brothers begin to decline, she worked with a financial planner to save as much money as possible and planned for an early retirement. Today, she’s still working part-time.
Glimmers of hope
For the study, the researchers recruited DIAN members who were cognitively normal or who had only mild symptoms, and who were in a window of time spanning 15 years before to 10 years after their estimated age of diagnosis. The researchers estimated the potential age at diagnosis by looking at the ages when other family members began showing symptoms.
For the first phase of the study, participants were randomly assigned to take either gantenerumab, another amyloid-lowering drug called solanezumab or a placebo. That study ran from the end of 2012 to the beginning of 2019.
At the end of that study, researchers allowed participants who had finished it to continue on gantenerumab in increasing doses for three years. That extension ran at 18 clinical trial sites in seven countries. In 2023, the drug’s sponsor, Roche, discontinued development of gantenerumab after disappointing study results made it unlikely to be approved by the FDA.
The study released Wednesday reports the results of this extension, in which all the participants – 73 – who continued on the therapy knew that they were on the drug.
Study participants who took gantenerumab during either the double-blind, placebo-controlled portion of the study or only in the open extension had a modest benefit. Their odds of developing symptoms were cut by about 20%, but the result was not statistically significant.
For the 22 people who had been on gantenerumab the longest – an average of eight years – the benefit was larger and at least partly statistically significant. The drug cut their risk of symptoms by almost half compared with people who were in an observational arm of the study, in which researchers were monitoring the progress of participants but not treating them.
Reiswig, like many members of his family, carries a mutation in a gene called presenilin-2, which causes his brain to overproduce amyloid plaques. His relatives who carry the mutation begin showing Alzheimer’s symptoms between ages 47 and 50. Reiswig is 46.
“I’m staring the gun right down the barrel,” he said.
His father also participated in DIAN in the observational arm but didn’t start the drug trial because he thought he was too sick to get any benefit. He died of Alzheimer’s in 2019, at the age of 66.
“That’s old for our family,” Reiswig said.
For years, Reiswig resisted finding out whether he carried the mutation, but he did get tested in 2020. When he learned that he had it, “I punched pillows, and I cried really hard,” Reiswig said. “It was the worst day ever.”
But “eventually, you run out of tears,” he said. He and his wife decided “we’re just going to get busy living,” because he didn’t know how many good years he might have after the age of 47.
Reiswig started in the solanezumab arm of the study and switched to gantenerumab in the extension.
He hasn’t seen any symptoms, but he also doesn’t know whether he’s actually getting any benefit from the drug.
More research is needed
Researchers who were not involved in the study said that even though it was small and not placebo-controlled, and the data is preliminary, it’s worth paying attention to.
“In the context of all we have learned about the value of amyloid removal in sporadic AD, these data are encouraging,” Dr. Paul Aisen, director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, wrote in an email.
Aisen led a study that tested solanezumab in people who had amyloid in their brains but didn’t have any symptoms. That study found no benefit to taking the drug, compared with a placebo, after more than four years of treatment.
Aisen believes that his study was negative because it tested a first-generation drug that didn’t remove amyloid as strongly as some of the newer ones do.
He’s now leading another study testing lecanemab in patients who don’t have symptoms. Because a long treatment period is required to see results in this stage of the disease, Aisen says they won’t have results until 2028 or 2029.
“Much more needs to be done, and additional major studies are in progress,” he wrote.
Others said the results from the latest research were hard to interpret, given the biases that probably exist in the study population.
“I don’t think there’s a clear signal here that this is working,” said Dr. Michael Greicius, a professor of neurology and neurological sciences at Stanford University who was not involved in the study.
Grecius said it’s difficult to compare this group of 22 people who continued on gantenerumab to people in the observational study, because people in the extension were able to join only if they finished the placebo-controlled trial. People who dropped out of the phase 3 study weren’t eligible to participate, which means participants in the extension had to be relatively healthy and doing better in the first place.
“These are big caveats,” Greicius said.
He says the biomarker data included in the paper shows that as the researchers increased the drug dosage, they were able to remove more amyloid from the brain.
But other biomarker data is less clear. PET imaging scans, for example, didn’t show much of a difference in the amounts of tau protein in the brain, even after extended treatment.
If there is a real effect here, Greicius says, it’s not likely to be a permanent one. “People are still progressing. They’re progressing more slowly than the control group.”
Even though this data comes with a lot of uncertainty – or perhaps because it comes with so much uncertainty – Greicius says it’s even more important to continue the research.
“This is an invaluable study population,” he said. “Continuing to follow them on treatment may provide the best test of the amyloid hypothesis that the field can undertake and stands to provide critical evidence either for or against it. This should be highly prioritized for continued funding.”
Reiswig said it would be devastating if the study had to be stopped due to lack of funding.
“Personally, I’m terrified of that. I’ll be taken off of a life-saving drug and left to wait until symptoms begin to begin slowing the disease with Kisunla or Leqembi,” he said.
He says he and the other DIAN participants have given decades of their lives to research, to developing a treatment, but then could be denied treatments they helped to test.
“Honestly, that feels criminal to me,” he said. “We are so close to preventing the world’s most tragic and expensive disease.”