Monoclonal antibody therapies can slow the progression of symptoms in people with Alzheimer’s disease, but it’s unclear if they can delay symptoms in those who show no signs yet. The DIAN-TU trial is ongoing, testing the safety and effectiveness of different treatments for people with a genetic form of Alzheimer’s disease.
Now, an experimental drug shows promising signs in reducing the risk of Alzheimer ‘s-related dementia in people destined to develop the disease in their 30s, 40s, or 50s. The findings from the DIAN-TU, which is based at Washington University School of Medicine in St. Louis, suggest that removing amyloid plaques from the brain well before symptoms can significantly delay the development of Alzheimer’s dementia.
The international study focused on 73 individuals with genetic mutations that lead to excessive amyloid production, making them highly likely to develop Alzheimer’s in middle age. Remarkably, for 22 participants without initial cognitive issues who took the drug for an average of eight years, the treatment reduced their risk of developing symptoms from nearly 100% to about 50%.
Senior author Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology at WashU Medicine, said, “Everyone in this study was destined to develop Alzheimer’s disease, and some of them haven’t yet. We don’t yet know how long they will remain symptom-free – maybe a few years or 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.”
The findings support the so-called amyloid hypothesis of Alzheimer’s disease, which suggests targeting the build-up of amyloid plaques in the brain and removing such plaques is the first step to treating dementia.
For this study, researchers evaluated the effects of an experimental anti-amyloid drug to determine if it can prevent the development of dementia.
The Knight Family DIAN-TU-001 trial was the world’s first attempt to prevent Alzheimer’s and started in 2012. It focused on testing anti-amyloid drugs in people with mild or no cognitive decline, all within 15 years before to 10 years after their expected Alzheimer’s onset based on family history.
The study found that gantenerumab—an anti-amyloid drug—reduced amyloid levels in the brain and improved Alzheimer’ s-related protein measures. However, researchers couldn’t confirm cognitive benefits in those without symptoms since participants hadn’t shown decline yet. To investigate further, they launched an extension to continue studying the drug, using higher doses and longer treatments to see if it could prevent or delay cognitive decline.
All participants in the DIAN-TU extension study had a high-risk genetic mutation for Alzheimer’s, regardless of their original treatment. Since everyone in the extension received gantenerumab, researchers used data from untreated individuals in a related study (DIAN Observational) and those from the DIAN-TU trial who didn’t join the extension as comparison groups.
The extension was planned for three years but ended early in mid-2023 after Roche/Genentech halted gantenerumab development in 2022. This decision followed Phase 3 trial results showing the drug didn’t significantly slow Alzheimer’s progression in early symptomatic cases. When it concluded, participants in the extension study had received treatment for an average of 2.6 years.
After analyzing the data, researchers found that removing brain amyloid plaques before the appearance of symptoms could delay symptom onset and dementia progression. However, the results were only statistically significant for the subgroup of people who started with no symptoms and were treated the longest.
No noticeable cognitive benefits have been observed so far for participants who received gantenerumab only during the extension study (for two to three years). In contrast, the group treated for an average of eight years showed that starting treatment well before symptoms may be crucial for preventing Alzheimer’s. This highlights the potential importance of early and prolonged intervention.
In the longest-treated group, the treatment reduced the risk of developing symptoms by 50%. This calculation considered how many participants developed symptoms and when they appeared relative to their expected onset age. The effect size may change over time—participants who remain symptom-free beyond their expected onset age will increase the effect size, while those who develop symptoms later may decrease it.
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Gantenerumab and similar drugs have a known side effect called amyloid-related imaging abnormalities (ARIA), detectable as tiny brain bleeds or swelling in scans. Most cases are mild and resolve without symptoms, but some are serious, and rare cases have led to deaths.
In this study, ARIA rates were higher (30% vs. 19%) due to higher doses in the extension. Two participants had severe ARIA but recovered after stopping the drug. No life-threatening events or deaths occurred, and the drug’s safety profile was similar to earlier trials.
To explore how long removing amyloid can delay dementia, WashU Medicine’s Knight Family DIAN-TU launched the Amyloid Removal Trial, funded by the Alzheimer’s Association and GHR Foundation. After gantenerumab was discontinued, most participants began taking lecanemab, an FDA-approved anti-amyloid drug for slowing cognitive decline in symptomatic patients.
Data from this phase are still being analyzed, and researchers have applied for NIH funding to complete the trial. The grant is currently under review.
Although the trial focused on genetic early-onset Alzheimer’s, Bateman and colleagues believe its findings will aid prevention and treatment for all types of Alzheimer’s. Early-onset and late-onset forms begin with amyloid building up in the brain about 20 years before cognitive issues appear. Additionally, results from early-onset trials have been confirmed in late-onset Alzheimer’s studies.
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“If late-onset Alzheimer’s prevention trials have similar results to the DIAN-TU trials, there soon could be Alzheimer’s preventions available for the general population,” Bateman said. “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.”
While gantenerumab is no longer being developed, other anti-amyloid drugs are being evaluated as preventive medications for Alzheimer’s disease.
“These exciting preliminary findings clearly hint at the potential role of lowering beta-amyloid in the prevention of Alzheimer’s disease,” said Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer and medical affairs lead.
“The Alzheimer’s Association looks forward with great anticipation to replication, extension, and expansion of this genuinely unprecedented and groundbreaking research, and we have made a significant investment in ensuring these important scientific questions can be investigated. 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.”
Journal Reference:
- Prof Randall J Bateman, Yan Li, Prof Eric M McDade 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, randomized, double-blind, placebo-controlled platform DIAN-TU trial. The Lancet Neurology. DOI: 10.1016/S1474-4422(25)00024-9
Source: Tech Explorist
