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

An experimental drug appears to reduce the risk of Alzheimer's-related dementia in people destined to develop the disease in their 30s, 40s or 50s, according to the results of a study led by the Knight Family Dominantly Inherited Alzheimer Network-Trials Unit (DIAN-TU), which is based at Washington University School of Medicine in St. Louis. The findings suggest – for the first time in a clinical trial – that early treatment to remove amyloid plaques from the brain many years before symptoms arise can delay the onset of Alzheimer's dementia.

The study is published March 19 in The Lancet Neurology.

The international study involved 73 people with rare, inherited genetic mutations that cause the overproduction of amyloid in the brain, all but guaranteeing that they will develop Alzheimer's disease in middle age. For a subgroup of 22 participants who had no cognitive problems at the study's start and who received the drug the longest – an average of eight years – the treatment lowered the risk of developing symptoms from essentially 100% to about 50%, according to a primary analysis of the data and supported by multiple sensitivity analyses supporting the trend.

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 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. 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."

Randall J. Bateman, MD, senior author, the 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 posits that the first step on the road to dementia is the build-up of amyloid plaques in the brain, and that removing such plaques or blocking their formation can stop symptoms from arising. For this study, Bateman and colleagues evaluated the effects of an experimental anti-amyloid drug to see if the medication could prevent the development of dementia.

The study population consisted of people who had originally enrolled in the Knight Family DIAN-TU-001, the first Alzheimer's prevention trial in the world, 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, 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 before to 10 years after their expected age of Alzheimer's onset, based on family history.

When the trial concluded in 2020, Bateman and colleagues reported that one of the drugs – gantenerumab, made by Roche and its U.S. affiliate, Genentech – lowered amyloid levels in the brain and improved some measures of Alzheimer's proteins. But the researchers did not see evidence of cognitive benefit yet because the group without symptoms – regardless of whether they were on drug or placebo – hadn't declined. These mixed results in the group without symptoms led the trial leaders to launch an open-label extension so the researchers could continue studying gantenerumab's effects and determine whether higher doses or longer treatment could prevent or delay cognitive decline.

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

Originally planned for three years, the extension was cut short in mid-2023 following the decision by Roche/Genentech to discontinue the development of gantenerumab in November 2022 after data from their pivotal Phase 3 GRADUATE I and II trials evaluating gantenerumab in people with early symptomatic Alzheimer's disease did not meet their primary endpoint of slowing clinical decline. The average participant in the extension trial had been treated for 2.6 years at the time it was terminated.

Analysis of this data set revealed that removal of brain amyloid plaques years before symptoms are expected to arise delayed symptom onset and dementia progression, although the results were only statistically significant for the subgroup of people who started with no symptoms and were treated the longest. For the group of participants who received gantenerumab only during the extension for two to three years because they had received another drug or placebo during the original trial, there have been no observable effects on cognitive function yet. The longest-treated group had received gantenerumab for eight years on average, suggesting that treatment years before onset may be necessary for prevention.

In the longest-treated group, the effect was strong: Treatment cut the risk of developing symptoms in half. This 50% effect size seen in the longest gantenerumab-treated group is the result of a calculation that takes into consideration not only how many people developed symptoms but when symptoms emerged for each participant compared to his or her expected age of onset. That means the effect size could change as time goes on. Some of the participants are at or just past their expected age of onset. The longer they go without developing symptoms, the greater the effect size will be. Conversely, some who are healthy now may develop symptoms down the road, reducing the effect size.

Gantenerumab and other anti-amyloid drugs have been linked to 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 aren't noticed by participants (that is, they show no symptoms) and resolve on their own, but a minority are more serious and, rarely, deaths have been linked to the side effect. In this study, ARIA rates were one-third higher than in the original clinical trial (30% vs 19%), which the researchers attribute to the higher doses used in the extension. Two participants developed such severe ARIA that they needed to be taken off the drug, at which point they recovered. There were no life-threatening adverse events and no deaths. Overall, the safety profile of gantenerumab in the extension was similar to that in the original trial and in other clinical trials of gantenerumab, the researchers said.

In order to answer the question of how long dementia can be delayed by removing amyloid, the Knight Family DIAN-TU, based at WashU Medicine, has launched the Knight Family DIAN-TU Amyloid Removal Trial, with initial funding from the Alzheimer's Association. Because gantenerumab was discontinued, most of the participants in the international open-label extension have started receiving lecanemab, an anti-amyloid drug approved by the Food and Drug Administration in 2023 to slow cognitive decline in people who already have 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 finish the trial. That grant is still pending NIH review.

While the trial was limited to people with genetic forms of Alzheimer's that lead to early onset, Bateman and colleagues expect that the study's results will inform prevention and treatment efforts for all forms of Alzheimer's disease. Both early-onset and late-onset Alzheimer's disease start with amyloid slowly collecting in the brain two decades before memory and thinking problems arise. Further, all trial results from these early-onset Alzheimer's mutation families have been replicated in late-onset Alzheimer's disease trials.

"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 hint very clearly at the potential role of lowering beta amyloid in 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."

The Knight Family DIAN-TU is evaluating the investigational amyloid-removing drug remternetug, made by Eli Lilly and Co., in the Primary Prevention Trial. Like the DIAN-TU secondary prevention trials, the Primary Prevention Trial involves members of families that carry dominant Alzheimer's mutations, but Primary Prevention participants are much younger. The trial is enrolling people as young as 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 ever taking hold.

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. 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.; Avid 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 gantenerumab open-label extension was supported by the Alzheimer's Association and F. Hoffman-LaRoche Ltd.

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH).