We might be on the precipice of a pivotal moment in Alzheimer’s disease research. In clinical trial data released this week, scientists have presented early evidence that it’s possible to delay symptoms in people genetically fated to develop Alzheimer’s at a young age.
Researchers at the Washington University School of Medicine led the study, which aimed to test whether an experimental anti-amyloid drug called gantenerumab could help people with an inherited form of Alzheimer’s. In a subset of patients treated the longest, the drug appeared to reduce their risk of developing symptoms as expected, by 50%. The findings will require a follow-up, but outside experts are cautiously optimistic about what this could mean for the future of treating Alzheimer’s.
“The results make it clear that there is good hope that treatment of [Alzheimer’s] pathology in the preclinical stages of pathology may be effective at slowing or preventing disease onset,” Thomas M. Wisniewski, the director of the Center for Cognitive Neurology at NYU Langone Health, who is not affiliated with the research, told Gizmodo.
Gantenerumab is one of many similar drugs that scientists have developed for Alzheimer’s. It’s a lab-made antibody that targets beta amyloid, one of two proteins thought to play a critical role in causing Alzheimer’s (the other being tau). In people with Alzheimer’s, a misfolded version of amyloid beta builds up in the brain, forming into hardy clumps known as plaques that eventually riddle the organ. Scientists have theorized that it’s possible to stop or at least slow down Alzheimer’s with drugs such as gantenerumab that break up and prevent these plaques from forming.
Unfortunately, it hasn’t been a smooth ride for this hypothesis. Many anti-amyloid drugs have shown promise early on, only to fail in larger trials that tested them for people already beginning to experience Alzheimer’s symptoms. That list includes gantenerumab; in late 2022, pharmaceutical company Roche shut down its development of the drug after a pair of Phase III trials failed.
But more recent anti-amyloid drugs have demonstrated a modest but noticeable effect in slowing down Alzheimer’s, enough to win approval from the Food and Drug Administration. Some researchers, including at WashU Medicine, hoped that anti-amyloid treatment could be more effective when administered long before the appearance of Alzheimer’s symptoms.
Starting in 2012, the researchers and others launched prevention trials testing anti-amyloid agents in people with dominantly inherited Alzheimer’s, a genetic condition that all but guarantees the development of dementia sometime between a person’s 30s and 50s. Most of these trials haven’t yielded success, except possibly for the one with gantenerumab.
When the original gantenerumab study concluded in 2020, the researchers found that it reduced people’s amyloid levels. But it was too early to know whether it might delay people’s symptoms, since most patients at the start of the study weren’t expected to become sick for another 10 to 15 years. The researchers then decided to openly provide gantenerumab to its patients (including those who were taking a placebo or another drug) as part of an extension study.
It’s the latest results from this study, published Wednesday in The Lancet Neurology, that has people excited.
“Everyone in this study was destined to develop Alzheimer’s disease and some of them haven’t yet,” said senior author Randall J. Bateman, a professor of neurology at WashU Medicine, in a statement from the university. “We don’t yet know how long they will remain symptom-free—maybe a few years or maybe decades.”
That said, there are important caveats to the study.
For one, the findings only hint at a potential preventative benefit, Wisniewski notes. Though the drug may have reduced the risk of cognitive decline in the overall larger group of symptomless people, this reduction wasn’t statistically significant (possibly because of the study’s low patient numbers, 73 in total, Wisniewski says). In the subset of asymptomatic patients who were treated the longest—about eight years on average—the drug seemed to reduce their expected chances of cognitive decline by 50%. But this subset only included 22 patients, an even smaller sample size.
The trial also ended earlier than expected for many patients due to Roche’s abandonment of the drug, and some people dropped out for other reasons. The drug appeared to be generally safe and tolerable, though about a third developed amyloid-related imaging abnormalities, or ARIAs, which are markers of swelling or bleeding of the brain. ARIAs are a known side-effect of these drugs, though most episodes are unnoticed by patients. Two patients did experience severe ARIAs, which prompted the researchers to stop treatment, after which they recovered. No life-threatening events or deaths were reported during the study.
All in all, the study is not definitive proof that anti-amyloid drugs can work for Alzheimer’s this far in advance. But since this form is essentially inevitable, these results are the first from a clinical trial to suggest it could be treated. Coupled with the earlier approvals of lecanemab and donanemab for the classical version of the neurodegenerative disorder, there does seem to be something real here.
“We already know from the lecanemab and donanemab data that anti-amyloid antibodies (AAAs) can slow progression of common, sporadic Alzheimer’s,” Sam Gandy, associate director of the Alzheimer’s Disease Research Center at Mount Sinai, told Gizmodo. “This paper focuses on using a different AAA (gantenerumab) to demonstrate a similar phenomenon is true in genetic early onset Alzheimer’s,” added Gandy, who’s not affiliated with the new research.
Gandy, Wisniewski, and the study researchers themselves all agree that this is only the beginning. There are indeed prevention trials ongoing right now for both early-onset and classic Alzheimer’s, including several being run by WashU through its Dominantly Inherited Alzheimer Network-Trials Unit. These trials are testing approved and newer experimental anti-amyloid drugs that could show even more of a protective benefit than gantenerumab. The researchers were also able to switch many of their patients in the original extension study to lecanemab, though the data from this phase remains to be analyzed.
It’s early days, but there might be genuine hope for this incurable disease on the horizon.
