Experimental drug shows promise for reducing risk of Alzheimer's-related dementia

Experimental drug shows promise for reducing risk of Alzheimer's-related dementia

An experimental drug appears to reduce the risk of Alzheimer's-related dementia in people who must develop the disease in their 30s, 40s or 50s, according to results of a study conducted by the Knight family in the Deliant Alzheimer Network Trials (Dian-Tu) at Washington University School of Medicine in St. Louis at Washington University of Medicine. The results suggest that - for the first time in a clinical trial - early treatment to remove amyloid plaques from the brain many years before symptoms appear can delay the onset of Alzheimer's dementia.

The study will be published on March 19thThe Lancet Neurology.

The international study included 73 people with rare, inherited genetic mutations that cause the overproduction of amyloid in the brain and guarantee that they will develop Alzheimer's disease in middle age. For a subgroup of 22 participants who had no cognitive problems at the start of the study and were on the drug for the longest time - an average of eight years - the treatment reduced the risk of developing symptoms from essentially 100% to about 50%. This emerges from a primary analysis of the data, supported by several sensitivity analyses.

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 - perhaps a few years or perhaps decades. To give them the best opportunity to remain cognitively normal, we continued treatment with another anti-amyloid antibody in the hope that they would never develop symptoms. What we do know is that it is possible to at least delay the onset of Alzheimer's disease symptoms and give people more years of healthy lives. “

Randall J. Bateman, MD, senior author, Charles F. and Joanne Knight Distinguished Professor of Neurology at Washu Medicine

The findings provide new evidence to support the so-called amyloid hypothesis of Alzheimer's disease, which suggests that the first step on the road to dementia is the buildup of amyloid plaques in the brain and that removing such plaques or blocking their formation can stop the symptoms from developing. For this study, Bateman and colleagues evaluated the effects of an experimental anti-amyloid drug to determine whether the drug could prevent the development of dementia.

The study population consisted of people who originally enrolled in Knight Family Dian-Tu-001, the world's first Alzheimer's prevention trial, and then continued into an extension of the trial in which they received an anti-amyloid drug. Currently led by Bateman and funded primarily by the Alzheimer's Association, the GHR Foundation and the National Institutes of Health (NIH), the Knight Family Dian-TU-001 was launched in 2012 to evaluate anti-amyloid drugs as preventive therapies for Alzheimer's disease. All participants in the trial had no to very mild cognitive decline and were within 15 years of their expected age of Alzheimer's disease starting from a family history.

When the study was completed in 2020, Bateman and colleagues reported that one of the drugs - gantenerumab, made by Roche and its US subsidiary Genentech - reduced amyloid levels in the brain and improved some measures of Alzheimer's proteins. However, the researchers did not see any evidence of cognitive benefit yet, as the group without symptoms - regardless of whether they were on drugs or placebo - did not decline. These mixed results in the asymptomatic group prompted investigators to launch an open-label extension so researchers could further study the effects of gantenerumab and determine whether higher doses or longer treatment can prevent or delay cognitive decline.

All Dian-TU participants who carried a high-risk Alzheimer's genetic mutation were eligible to enter the extension study, regardless of whether they had received gantenerumab, another drug or a placebo during the trial. Because all participants in the expansion received the experimental drug, there was no internal control group. Instead, researchers compared the expansion participants with people in a related study known as the Dian observation who had not received drug treatment and with placebo-treated Dian-TU participants who did not continue into the expansion.

Originally planned for three years, the expansion was completed in mid-2023 following Roche/Genentech's decision to discontinue development of gantenerumab in November 2022 after data from their pivotal Phase 3 graduate I and II trials evaluating ganzerumab in people with early symptomatic Alzheimer's disease failed to slow clinical decline. The average participant in the extension study had been treated for 2.6 years at the time of termination.

Analysis of this data set found that removing brain amyloid plaques years before expected symptoms will delay symptoms and dementia progression, although the results were only statistically significant for the subgroup of people with the symptoms and treated for the longest period of time. For the group of participants who received gantenerumab only during the expansion for two to three years because they had received another drug or a different placebo during the original study, there were still no observable effects on cognitive function. The longest-treated group had received gantenerumab for an average of eight years, suggesting that years of treatment may be necessary before starting prevention.

In the group treated for the longest time, the effect was strong: treatment reduced the risk of developing symptoms in half. This 50% effect size observed in the group treated with gantenerumab for the longest time is the result of a calculation that takes into account not only how many people developed symptoms, but when symptoms appeared for each participant compared to their expected age of onset. This means that the effect size could change over time. Some of the participants are in their expected age of beginning. The longer they go without symptoms, the larger the effect size becomes. Conversely, some who are now healthy may develop symptoms down the road, reducing the effect size.

Gantenerumab and other anti-amyloid drugs have been associated with a side effect known as amyloid-related imaging abnormalities, or aria. The abnormalities are detectable on brain scans and represent tiny spots of blood in the brain or localized swelling of the brain. In clinical trials, most cases of ARIA go unnoticed by participants (that is, they show no symptoms) and resolve on their own, but a minority are more serious and rarely deaths are associated with the side effect. In this study, ARIA rates were a third higher than in the original clinical trial (30% versus 19%), which the researchers attribute to the higher doses used in the expansion. Two participants developed an aria so severe that they had to be taken off the medication, at which point they recovered. There were no life-threatening adverse events and no deaths. Overall, the safety profile of gantenerumab in the expansion was similar to that in the original study and in other clinical trials of gantenerumab, the researchers said.

To answer the question of how long dementia can be delayed by removing amyloid, Washu Medicine-based Knight Family Dian-Tu launched Knight Family Dian-tu Amyloid Removal with initial funding from the Alzheimer's Association. Since gantenerumab has been discontinued, most participants in the international open-label expansion will receive lecanemab, a Food and Drug Administration-approved anti-amyloid drug, in 2023 to slow cognitive decline in people with symptoms of Alzheimer's disease. Data from this phase of the extension trial have not yet been analyzed. Washu Medicine researchers have submitted an NIH grant that, if approved, would provide funding to complete the trial. This grant is pending NIH review.

While the study was limited to people with genetic forms of Alzheimer's disease that cause early onset, Bateman and colleagues expect the study's results to influence prevention and treatment efforts for all forms of Alzheimer's disease. Both early and late Alzheimer's disease begin to appear slowly in the brain two decades before memory and thinking problems. Additionally, all study results from these early Alzheimer's disease mutation families have been replicated in late Alzheimer's disease trials.

"If the late-onset Alzheimer's prevention trials have similar results to the Dian Tu trials, there could soon be Alzheimer's prevention for the general population," Bateman said. "I am very optimistic now that this could be the first clinical evidence of what could become preventative measures for people at risk for Alzheimer's disease. One day we will delay the onset of Alzheimer's disease for millions."

While gantenerumab is no longer in development, other anti-amyloid drugs are being studied as preventive drugs for Alzheimer's.

“These exciting preliminary findings strongly suggest the potential role of lowering amyloid beta in the prevention of Alzheimer's disease,” said Maria C. Carrillo, PhD, Alzheimer's Association chief science officer and medical affairs. "The Alzheimer's Association looks forward with great anticipation to replicating, expanding and expanding this truly unprecedented and groundbreaking research, and we have made a significant investment in ensuring these important scientific questions can be investigated. Discoveries like these illustrate why it is so important for research into Alzheimer's and all diseases that deny themselves to grow and expand and expand."

The Knight Family Dian-Tu evaluates the investigational amyloid-renotic drugs manufactured by Eli Lilly and Co. in the primary prevention study. As with the Dian-Tu Secondary Prevention Trials, the primary prevention trial includes family members who carry the dominant Alzheimer's mutations, but the primary prevention participants are much younger. The trial includes people ages 18 who have few or no detectable Alzheimer's-related molecular changes in their brains, up to 25 years before the expected onset of dementia symptoms, to determine whether stopping the early molecular changes that lead to symptomatic Alzheimer's disease can prevent the disease from becoming more prevalent.

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 multicenter phase 2/3, randomized, double-blind, placebo-controlled Dian-TU trial. The Lancet Neurology. March 19, 2025.

The DIAN-TU-001 portion of this study was funded by grants from the National Institutes of Health’s National Institute on Aging (grant numbers U01AG042791, U01AG042791-S1 (FNIH and Accelerating Medicines Partnership), R01AG046179, R01AG053267, R01AG053267-S1 and R01AG053267-S2); the Alzheimer's Association; Eli Lilly and Company; F. Hoffman-Laroche Ltd.; Enthusiastic Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly and Company); GHR Foundation; an anonymous organization; Cerveau Technologies; Cogstate and Signant. The Dian-tu has also received funding from the Dian-tu Pharma Consortium. The open-label expansion of gantenerumab was approved by the Alzheimer Association and F. Hoffman-Laroche Ltd. supports.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health (NIH).

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