Discontinued Alzheimer’s Drug Shows Potential for Disease Prevention in High-Risk Groups

An experimental Alzheimer’s drug, gantenerumab, may delay the onset of Alzheimer's disease in people with inherited risk, according to a new study led by the Knight Family Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) at Washington University School of Medicine in St. Louis.

Published in The Lancet Neurology, the study found that long-term treatment with gantenerumab reduced the risk of developing symptoms by 50% in certain patients.

Rethinking Alzheimer's prevention

Dementia affects over 55 million people worldwide, with Alzheimer's disease accounting for 60–70% of cases. As populations age, this number is projected to triple by 2050, making Alzheimer's the leading cause of cognitive decline and loss of independence. Despite decades of research, the disease remains incurable and available treatments offer only modest benefits.

Currently approved Alzheimer’s drugs, such as cholinesterase inhibitors and memantine, are designed to alleviate symptoms rather than address the underlying pathology. They can temporarily improve cognition or reduce symptoms of agitation but do not halt or reverse disease progression.

For years, scientists have pursued a different approach based on the amyloid hypothesis, which suggests that Alzheimer’s begins with the accumulation of amyloid-beta plaques in the brain – triggering a cascade of neuronal damage and cognitive decline. The hypothesis suggests that removing amyloid plaques or blocking their formation could prevent or delay the onset of Alzheimer's. Yet, despite the theoretical appeal of this approach, clinical trials targeting amyloid have been riddled with failures.

Anti-amyloid drugs are typically monoclonal antibodies designed to recognize and clear amyloid plaques from the brain. Some of the most well-known candidates, including aducanumab, lecanemab and donanemab, have shown limited success in reducing plaque levels and cognitive improvements have proven challenging to come by.

Alzheimer’s drug shows potential, but challenges remain

The study aimed to investigate whether early removal of amyloid plaques could delay the onset of Alzheimer’s symptoms in individuals genetically predisposed to develop the disease in their 30s, 40s or 50s. The trial included 73 participants with rare inherited mutations known to cause early-onset Alzheimer's. These participants were either asymptomatic or mildly symptomatic at the study's onset. The study was designed as an open-label extension of the Phase II/III multi-center, randomized, double-blind, placebo-controlled DIAN-TU-001 trial. The primary focus was to assess the long-term safety and efficacy of high dose gantenerumab treatment, with doses reaching 1500 mg every 2 weeks.

In a subgroup of 22 participants, who remained cognitively normal at the start and received the drug for an average of 8 years, the risk of developing symptoms was reduced by 50%.

“Everyone in this study was destined to develop Alzheimer’s disease and some of them haven’t yet,” said lead author Dr. Randall J. Bateman, the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University School of Medicine in St. Louis.

However, the study’s promising results come with significant caveats. The statistical significance was only reached for the longest-treated subgroup and no noticeable cognitive benefits were observed for participants who received the drug for a shorter period.

Safety concerns also remain prominent, with the incidence of amyloid-related imaging abnormalities (ARIA) being higher in the extension trial than in the original clinical trial – 30% vs 19%. This raises questions about the broader safety of long-term high-dose treatment.

Adding to the complexity is the decision by Roche/Genentech to discontinue gantenerumab development after the GRADUATE I and II trials failed to meet their primary endpoints of slowing clinical decline. This decision casts doubt on the broader viability of gantenerumab, despite the encouraging findings from the original trial

“We don’t yet know how long they will remain symptom-free – maybe a few years or maybe decades. 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. What we do know is that it’s possible at least to delay the onset of the symptoms of Alzheimer’s disease and give people more years of healthy life.”

Dr. Randall J. Bateman

What does this mean for Alzheimer’s treatment?

The results of the trial, despite their limitations, underline the potential benefits of early intervention in preventing or delaying Alzheimer’s disease. The most positive outcomes occurred in those treated years before symptoms emerged, reinforcing the idea that therapeutic success might depend on catching the disease in its earliest stages.

The study’s focus on pre-symptomatic individuals highlights a shift in how Alzheimer’s might be approached. Instead of waiting for cognitive decline to set in, there is growing interest in identifying at-risk individuals earlier and starting preventative treatment before significant brain damage occurs.

Meanwhile, as gantenerumab is no longer being developed, researchers are pivoting to other promising candidates like lecanemab, which received FDA approval in 2023 for slowing cognitive decline in symptomatic patients. Ongoing trials are now investigating whether similar benefits might extend to asymptomatic or pre-symptomatic individuals.

“If late-onset Alzheimer’s prevention trials have similar results to the DIAN-TU trials, there soon could be Alzheimer’s prevention available for 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 for Alzheimer’s disease. One day soon, we may be delaying the onset of Alzheimer’s disease for millions,” said Bateman.

“These exciting preliminary findings hint very clearly at the potential role of lowering beta-amyloid in the prevention of Alzheimer’s disease. Discoveries like this convincingly illustrate why it is so important for research into Alzheimer’s and all diseases that cause dementia to continue, expand and accelerate,” said Dr. Maria C. Carrillo, Alzheimer’s Association chief science officer and medical affairs lead.

Despite the promising findings, it remains unclear whether complete amyloid removal will consistently translate to a meaningful delay in cognitive decline. Long-term studies are necessary to determine whether such interventions can offer widespread clinical benefit and whether the safety profile of these therapies can be improved.

Reference: Bateman RJ, Li Y, McDade EM, et al. Safety and efficacy of long-term gantenerumab treatment in dominantly inherited Alzheimer’s disease: an open-label extension of the phase 2/3 multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU trial. The Lancet Neurology. 2025;24(4):316-330. doi: 10.1016/S1474-4422(25)00024-9

This article is a rework of a press release issued by Washington University School of Medicine in St. Louis. Material has been edited for length and content.