Alzheimer’s Disease Research: A Potential Breakthrough

We may be on the cusp of a pivotal moment in Alzheimer’s disease research. Recently released clinical trial data presents early evidence that it is possible to delay symptoms in individuals genetically fated to develop Alzheimer’s at a young age.

The Study

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%. While the findings require follow-up, outside experts are cautiously optimistic about the potential implications 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," said Thomas M. Wisniewski, the director of the Center for Cognitive Neurology at NYU Langone Health, who is not affiliated with the research.

Gantenerumab: A Promising Treatment

Gantenerumab is one of many similar drugs developed for Alzheimer’s. It is a lab-made antibody that targets beta amyloid, one of two proteins thought to play a critical role in causing Alzheimer’s. In people with Alzheimer’s, a misfolded version of amyloid beta builds up in the brain, forming hardy clumps known as plaques that eventually riddle the organ. Scientists have theorized that it is possible to stop or at least slow down Alzheimer’s with drugs such as gantenerumab that break up and prevent these plaques from forming.

A Complex History

However, it has not 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. Gantenerumab is no exception; in late 2022, pharmaceutical company Roche shut down its development of the drug after a pair of Phase III trials failed.

Recent Developments

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 those at WashU Medicine, hoped that anti-amyloid treatment could be more effective when administered long before the appearance of Alzheimer’s symptoms.

The Trial

Starting in 2012, researchers 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 have not yielded success, except possibly for the one with gantenerumab.

Exciting Results

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 were not expected to become sick for another 10 to 15 years. The researchers then decided to openly provide gantenerumab to its patients as part of an extension study.

"Everyone in this study was destined to develop Alzheimer’s disease and some of them haven’t yet."

The latest results from this study, published in The Lancet Neurology, have 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. "We don’t yet know how long they will remain symptom-free—maybe a few years or maybe decades."

Caveats and Future Directions

While the study is promising, there are important caveats to consider. The findings only hint at a potential preventative benefit, and the reduction in cognitive decline was only statistically significant in a subset of asymptomatic patients who were treated the longest. 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.

Despite these limitations, the study is not definitive proof that anti-amyloid drugs can work for Alzheimer’s this far in advance. However, 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 can slow progression of common, sporadic Alzheimer’s," said Sam Grady, associate director of the Alzheimer’s Disease Research Center at Mount Sinai. "This paper focuses on using a different antibody to demonstrate a similar phenomenon is true in genetic early-onset Alzheimer’s."

Conclusion

While it is early days, there might be genuine hope for this incurable disease on the horizon. Ongoing prevention trials for both early-onset and classic Alzheimer’s, including several being run by WashU, will continue to test approved and newer experimental anti-amyloid drugs that could show even more of a protective benefit than gantenerumab. As researchers continue to explore the potential of anti-amyloid drugs, there is a growing sense of optimism that a breakthrough may be within reach.