Trial of Lilly drug in young people at risk of Alzheimer’s aims to prevent build up of amyloid plaque and interrupt the disease at its origin.
The first participants have been enrolled in a groundbreaking Alzheimer’s trial that aims to intervene in the disease decades before symptoms arise, rather than attempting to slow disease progression after cognitive decline has begun. Led by Washington University School of Medicine in St Louis, the trial is investigating whether an investigational antibody developed by Eli Lilly can prevent the accumulation of amyloid beta plaques in the brains of young adults at high genetic risk for the disease.
The trial is recruiting participants as young as 18, carrying genetic mutations that all but guarantee the development of early-onset Alzheimer’s. These mutations cause the disease to manifest in a person’s 30s, 40s or 50s, but the earliest molecular changes – particularly the accumulation of amyloid beta – begin up to 25 years before symptoms appear. By targeting these plaques in individuals who have no cognitive impairment and little to no detectable amyloid in their brains, researchers hope to interrupt the disease process at its very origin.
The work builds on recent progress in Alzheimer’s treatment, specifically in amyloid-targeting drugs for individuals with mild cognitive impairment or early-stage Alzheimer’s. The new study seeks to take this a step further by testing whether intervention at an earlier stage can potentially prevent symptoms altogether.
“We have seen tremendous progress in the treatment of Alzheimer disease in the past few years,” said Eric McDade, professor of neurology at WashU Medicine and the trial’s principal investigator. “Two amyloid-targeting drugs were shown to slow symptoms of the disease and have now been approved by the FDA as treatments for people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. This provides strong support for our hypothesis that intervening when amyloid beta plaques are at the very earliest stage, long before symptoms arise, could prevent symptoms from emerging in the first place.”
The study’s original plan was to test a drug called gantenerumab, developed by Roche/Genentech. However, after disappointing trial results led its development to be discontinued, Eli Lilly’s remternetug was selected as a replacement. The drug has already demonstrated robust amyloid plaque removal in early-stage clinical trials.
Participants will undergo treatment for two years, with researchers monitoring amyloid buildup through brain scans and analyzing molecular markers of Alzheimer’s in their blood and cerebrospinal fluid. Since the study’s participants are young and asymptomatic, cognitive changes are not expected during the trial’s timeframe. However, the research team plans to follow participants long-term to assess whether this early intervention has a measurable impact on cognition later in life. At the conclusion of the study, those who carry the genetic mutation will have the option to continue receiving the drug for an additional four years as part of an open-label extension.
“My grandfather passed away from Alzheimer’s, and so did his mother and all but one of his brothers,” said Hannah Richardson, 24, a participant in the trial. “My mom and my uncle have been participating in DIAN trials since I was about 10 years old. My mom was always very open about her diagnosis and how it spurred her advocacy for Alzheimer’s research, and I’ve always known I wanted to follow in her footsteps. I am happy to be involved in the Primary Prevention Trial and be involved in research because I know how important it is.”
The trial is expected to enroll approximately 240 participants worldwide. Both individuals who have inherited the Alzheimer’s-linked mutation and those who have not are eligible to participate, with the latter serving as a comparison group. To qualify, participants must be between 11 and 25 years younger than the expected onset of symptoms in their family and have no cognitive impairment.
