Promising Experimental Drug Shows Potential in Preventing Alzheimer’s in High-Risk Individuals
A new study from Washington University School of Medicine in St. Louis offers a glimmer of hope in the fight against Alzheimer’s disease. Researchers have found that an experimental drug, gantenerumab, shows promise in preventing the onset of Alzheimer’s symptoms in individuals with rare genetic mutations that virtually guarantee the development of the disease.
The study, published in the journal The Lancet Neurology on March 19, focused on individuals in their 30s, 40s, and 50s who carry a specific genetic mutation leading to an overproduction of amyloid in the brain. Amyloid, a protein that accumulates in the brain and disrupts cognitive function, is a hallmark of Alzheimer’s disease. All participants had a family history of Alzheimer’s and were either within 15 years before or 10 years after their anticipated age of symptom onset, exhibiting no or very mild cognitive decline at the study’s outset.
The researchers administered gantenerumab, a monoclonal antibody designed to target and eliminate amyloid plaques in the brain, to a subset of the participants. After eight years of treatment, the results were striking. The risk of developing Alzheimer’s symptoms was cut in half for those who received the drug, dropping from an expected 100% to 50%. However, the study found no discernible effect in participants who received only two to three years of treatment, emphasizing the importance of prolonged intervention.
"Everyone in this study was destined to develop Alzheimer’s disease, and some of them haven’t yet," explained senior author Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished 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. In order to give them the best opportunity to stay cognitively normal, we have continued treatment with another anti-amyloid antibody in hopes they will never develop symptoms at all."
Despite the encouraging findings, the development of gantenerumab by Roche in Switzerland and its U.S. affiliate, Genentech, was halted in 2023. The decision came after Roche/Genentech’s own clinical trials failed to meet their primary endpoint of slowing cognitive decline in people with early symptomatic Alzheimer’s disease. This discrepancy highlights the complexities of Alzheimer’s research and the potential differences in drug efficacy depending on the stage of disease progression.
Despite the setback with gantenerumab’s development, the Washington University study offers a significant breakthrough. "What we do know is that it’s possible to at least delay the onset of the symptoms of Alzheimer’s disease and give people more years of healthy life," Bateman stated. He expressed optimism that similar results in trials focusing on late-onset Alzheimer’s could pave the way for prevention methods accessible to the general population. "I am highly optimistic now, as this could be the first clinical evidence of what will become preventions for people at risk of Alzheimer’s disease," he added. "One day soon, we may be delaying the onset of Alzheimer’s disease for millions."
Howard Fillit, MD, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation in New York, who was not involved in the study, echoed this sentiment. He emphasized that the study provides the first evidence that early treatment aimed at clearing amyloid plaques before symptom onset can effectively delay the development of Alzheimer’s disease, a strategy mirroring the approach to managing other chronic conditions. "We’ve entered into a new era of Alzheimer’s research where we can not only modify the course of the disease, but where prevention is possible with therapeutic intervention," Fillit remarked.
The study also acknowledges its limitations. The number of participants was constrained by the rarity of Alzheimer’s disease caused by genetic mutations, the use of external controls, and the gradual increase in dosage at the beginning of the trial. Bateman also noted that many participants remain cognitively normal, even surpassing their expected age of onset after eight years of treatment, suggesting that continued treatment and follow-up may reveal larger or smaller effects.
Another crucial consideration is the potential for amyloid-related imaging abnormalities (ARIA), a known side effect of anti-amyloid medications like gantenerumab. ARIA manifests as tiny spots of blood or localized swelling in the brain, detectable through brain scans. While most cases are asymptomatic and resolve without intervention, severe cases can lead to significant medical problems or even death. In the study, 30% of participants experienced ARIA, likely attributed to the higher drug doses used. Although two participants had to discontinue gantenerumab due to severe ARIA, there were no life-threatening events or fatalities.
Dr. Chris Vercammen, a board-certified internal medicine physician specializing in geriatrics and palliative care, emphasized the need for further research to confirm the initial findings. "Large, randomized trials, including diverse populations and individuals with late-onset Alzheimer’s, are needed to validate these early results and determine the full potential of these treatments," Vercammen stated. He also cautioned that the study’s focus on high-risk individuals in the preclinical stage limits its applicability to later-stage Alzheimer’s disease.
Despite these limitations, the study’s implications are profound. Fillit emphasized that the research opens avenues for exploring treatment strategies for preclinical Alzheimer’s. "We look forward to seeing the longitudinal data as well as further studies around this approach," he said. "These efforts bring us one step closer to our ultimate goal of preventing the disease before it begins."
While gantenerumab is no longer under development, researchers are exploring other anti-amyloid drugs, such as remternetug, manufactured by Eli Lilly, to determine their potential in preventing Alzheimer’s disease. Bateman encouraged families with relevant genetic mutations to consider participating in ongoing trials. He also noted the existence of ongoing trials for individuals with amyloid plaques, aimed at determining whether Alzheimer’s symptoms can be prevented through this approach.
The study was primarily funded by the Alzheimer’s Association, GHR Foundation, and the National Institutes of Health (NIH).
