An investigational medication seems to diminish the likelihood of Alzheimer’s-associated dementia in individuals who are likely to develop the disorder in their 30s, 40s, or 50s, based on the outcomes of a study spearheaded by the Knight Family Dominantly Inherited Alzheimer Network-Trials Unit (DIAN-TU), situated at Washington University School of Medicine in St. Louis. The results indicate — for the first time in a clinical trial — that initiating treatment to eliminate amyloid plaques from the brain many years prior to the onset of symptoms can postpone the arrival of Alzheimer’s dementia.
The research is featured in the March 19 edition of The Lancet Neurology.
The global study included 73 individuals with unique, hereditary genetic mutations leading to excessive amyloid production in the brain, effectively ensuring they will develop Alzheimer’s disease in middle age. For a subgroup comprising 22 participants who exhibited no cognitive issues at the onset of the study and who underwent the longest duration of treatment — an average of eight years — the intervention decreased the risk of manifesting symptoms from nearly 100% to around 50%, as per a primary analysis of the data, supported by numerous sensitivity analyses reinforcing this trend.
“Each participant in this trial was fated to develop Alzheimer’s disease, and some of them remain symptom-free,” mentioned senior author Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology at WashU Medicine. “We still do not know how long they will stay symptom-free — it could be a few years or perhaps decades. To provide them the best chance to maintain cognitive normalcy, we have continued treatment with an alternative anti-amyloid antibody, hoping they may never exhibit symptoms at all. What we do know is that it is feasible at least to postpone the onset of Alzheimer’s disease symptoms, granting individuals more years of healthy living.”
The findings offer fresh evidence supporting the amyloid hypothesis concerning Alzheimer’s disease, which asserts that the initial step toward dementia involves the accumulation of amyloid plaques in the brain, and that eliminating or obstructing the formation of such plaques can prevent symptoms from manifesting. For this research, Bateman and teammates examined the ramifications of an experimental anti-amyloid medication to ascertain if it could avert the development of dementia.
The study cohort comprised individuals who had initially signed up for the Knight Family DIAN-TU-001, the world’s first Alzheimer’s prevention trial, before advancing into a trial extension in which they received an anti-amyloid medication. Currently overseen by Bateman and primarily funded by the Alzheimer’s Association, GHR Foundation, and the National Institutes of Health (NIH), the Knight Family DIAN-TU-001 was initiated in 2012 to assess anti-amyloid drugs as preventative measures for Alzheimer’s disease. All trial participants exhibited no or very mild cognitive decline, and were within a range of 15 years before to 10 years after their anticipated age of Alzheimer’s onset, according to familial history.
Upon the trial’s conclusion in 2020, Bateman and associates stated that one of the medications — gantenerumab, produced by Roche and its U.S. partner, Genentech — reduced amyloid levels in the brain and improved various metrics of Alzheimer’s proteins. However, the researchers did not observe any signs of cognitive advantages as the symptom-free group — regardless of whether they received the drug or a placebo — had not declined. These inconclusive outcomes within the asymptomatic group prompted the trial leaders to initiate an open-label extension, allowing researchers to continue investigating gantenerumab’s impacts and determine if higher dosages or extended treatment could prevent or slow cognitive decline.
All DIAN-TU participants possessing a high-risk Alzheimer’s genetic mutation were permitted to proceed into the extension study, regardless of whether they had previously received gantenerumab, another medication, or a placebo during the initial trial. Since every participant in the extension received the experimental drug, there was no internal control group. Instead, the researchers compared extension participants to individuals in a related study known as the DIAN Observational who had not received any drug treatment, and to placebo-administered DIAN-TU participants who opted not to transition into the extension.
Initially intended to last three years, the extension was abruptly concluded in mid-2023 following Roche/Genentech’s decision to halt gantenerumab development in November 2022 after their pivotal Phase 3 GRADUATE I and II trials assessing gantenerumab in patients with early symptomatic Alzheimer’s disease failed to achieve the primary objective of reducing clinical decline. At the time of termination, the average participant in the extension trial had been treated for 2.6 years.
Analysis of this data revealed that the elimination of brain amyloid plaques several years before anticipated symptoms can defer symptom onset and dementia progression, although the results were statistically significant only for the subgroup of participants who began without symptoms and were treated for the longest duration. For those individuals who received gantenerumab solely during the extension for two to three years, due to having been administered another medication or placebo in the original trial, no notable effects on cognitive functioning have yet been observed. The group with the longest treatment received gantenerumab for an average of eight years, indicating that early intervention may be essential for prevention.
In the longest-treated group, the effect was profound: Treatment halved the risk of symptom development. The 50% effect size observed in the longest gantenerumab-treated cohort results from a calculation that considers not just how many individuals developed symptoms, but also the timing of symptom emergence for each participant relative to their expected age of onset. This implies that the effect size may change over time. Some participants are at or have surpassed their anticipated age of onset; the longer they continue without developing symptoms, the greater the effect size will be. Conversely, some currently healthy individuals may exhibit symptoms later, which would diminish the effect size.
Gantenerumab and other anti-amyloid medications have been associated with a side effect known as amyloid-related imaging abnormalities, or ARIA. These abnormalities are identifiable on brain scans and represent small areas of bleeding in the brain or localized brain swelling. In clinical trials, most ARIA cases go unnoticed by participants (they exhibit no symptoms) and resolve naturally, though a minority are more severe, and deaths have, albeit rarely, been connected to this side effect. In this investigation, ARIA rates were one-third higher compared to the original clinical trial (30% vs 19%), which the researchers attribute to the elevated doses employed during the extension. Two participants experienced such severe ARIA that they required discontinuation of the drug, after which they made a full recovery. There were no life-threatening adverse incidents nor fatalities. Overall, the safety profile of gantenerumab in the extension was comparable to that in the original trial and other gantenerumab clinical trials, according to the researchers.
To address the inquiry regarding how long dementia can be postponed by removing amyloid, the Knight Family DIAN-TU, based at WashU Medicine, has initiated the Knight Family DIAN-TU Amyloid Removal Trial, initially funded by the Alzheimer’s Association. Due to the discontinuation of gantenerumab, the majority of participants in the international open-label extension have begun receiving lecanemab, an anti-amyloid medication approved by the Food and Drug Administration in 2023 to slow cognitive decline in individuals already exhibiting symptoms of Alzheimer’s.
disease. Data from this stage of the extension trial have yet to be examined. Researchers at WashU Medicine have applied for an NIH grant which, if granted, would supply resources to complete the trial. This application is currently awaiting NIH evaluation.
Although the trial was restricted to individuals with hereditary forms of Alzheimer’s that result in early onset, Bateman and his team anticipate that the findings of this study will contribute to prevention and treatment strategies for all variants of Alzheimer’s disease. Both early-onset and late-onset Alzheimer’s diseases commence with amyloid gradually accumulating in the brain up to two decades before cognitive and memory issues become apparent. Moreover, all trial outcomes from these early-onset Alzheimer’s mutation families have shown similar results in late-onset Alzheimer’s trials.
“If prevention trials for late-onset Alzheimer’s yield results akin to those of the DIAN-TU trials, effective Alzheimer’s preventatives could soon be accessible for the general populace,” Bateman stated. “I am very hopeful at this moment, as this may provide the initial clinical evidence for what could ultimately become preventions for individuals at risk of Alzheimer’s disease. Soon, we might be able to postpone the onset of Alzheimer’s disease for millions.”
Though gantenerumab is no longer under development, other anti-amyloid medications are being assessed as preventive treatments for Alzheimer’s disease.
“These thrilling preliminary results strongly indicate the potential importance of reducing beta amyloid in the prevention of Alzheimer’s disease,” remarked Maria C. Carrillo, PhD, chief science officer and medical affairs lead at the Alzheimer’s Association. “The Alzheimer’s Association eagerly anticipates the replication, extension, and expansion of this truly unprecedented and groundbreaking research, and we have invested significantly to facilitate inquiries into these essential scientific questions. Discoveries like this effectively highlight the necessity for ongoing, expanding, and accelerating research into Alzheimer’s and all dementias.”
The Knight Family DIAN-TU is assessing the experimental amyloid-clearing medication remternetug, produced by Eli Lilly and Co., in the Primary Prevention Trial. Similar to the DIAN-TU secondary prevention trials, the Primary Prevention Trial includes family members carrying dominant Alzheimer’s mutations, but the participants in Primary Prevention are significantly younger. The trial is recruiting individuals as young as 18 who present few or no observable Alzheimer’s-related molecular alterations in their brains, up to 25 years ahead of the anticipated emergence of dementia symptoms, to explore whether halting the initial molecular modifications that lead to symptomatic Alzheimer’s can prevent the disease from manifesting entirely.
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 segment of this research received funding from grants provided by 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 undisclosed organization; Cerveau Technologies; Cogstate and Signant. The DIAN-TU has additionally received funding from the DIAN-TU Pharma Consortium. Support for the gantenerumab open-label extension was provided by the Alzheimer’s Association and F. Hoffman-LaRoche Ltd.
The information presented in this article reflects the authors’ perspectives and does not necessarily represent the official stance of the National Institutes of Health (NIH).
About Washington University School of Medicine
WashU Medicine is a worldwide pioneer in academic medicine, encompassing biomedical research, patient care, and educational programs with a faculty of 2,900. Its National Institutes of Health (NIH) research funding portfolio ranks second largest among U.S. medical schools and has surged by 56% over the past seven years. Alongside institutional funding, WashU Medicine commits over $1 billion each year to innovative basic and clinical research and training. The faculty practice consistently remains among the top five nationwide, with more than 1,900 faculty physicians serving at 130 sites and also part of the medical teams of Barnes-Jewish and St. Louis Children’s hospitals of BJC HealthCare. WashU Medicine has a distinguished history in MD/PhD training, recently dedicating $100 million to scholarships and curriculum renewal for its medical scholars, and hosts outstanding training programs across various medical subspecialties, in addition to physical therapy, occupational therapy, and audiology and communications sciences.
Originally published on the WashU Medicine website
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