According to the findings of a study conducted by the Knight Family Dominantly Inherited Alzheimer Network-Trials Unit (DIAN-TU), located at Washington University School of Medicine in St. Louis, an experimental medication appears to lower the risk of Alzheimer’s-related dementia in individuals who are destined to develop the disease in their 30s, 40s, or 50s. For the first time in a clinical experiment, the results imply that Alzheimer’s dementia can be postponed by receiving early treatment to remove amyloid plaques from the brain years before symptoms appear.
73 participants in the global study had uncommon, hereditary genetic abnormalities that result in an excess of amyloid in the brain, virtually ensuring that they will get Alzheimer’s in their middle years. According to a primary analysis of the data and several sensitivity analyses confirming the trend, the treatment reduced the risk of developing symptoms from nearly 100% to roughly 50% for a subgroup of 22 participants who had no cognitive issues at the beginning of the study and who received the drug the longest, on average for eight years.
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
The results offer fresh evidence in favor of the so-called amyloid theory of Alzheimer’s disease, which holds that the accumulation of amyloid plaques in the brain is the initial cause of dementia and that preventing or removing these plaques can prevent symptoms from developing. In order to determine whether an experimental anti-amyloid medicine may stop dementia from developing, Bateman and colleagues conducted this investigation.
The study population was made up of individuals who had first signed up for the world’s first Alzheimer’s prevention trial, Knight Family DIAN-TU-001, and then continued onto an extension of the trial where they were given an anti-amyloid medication. The Knight Family DIAN-TU-001 was established in 2012 to assess anti-amyloid medications as preventive treatments for Alzheimer’s disease. It is currently headed by Bateman and is mainly supported by the National Institutes of Health (NIH), the GHR Foundation, and the Alzheimer’s Association. Based on family history, all trial participants had no to very modest cognitive loss and were between 15 and 10 years before or after the age at which Alzheimer’s disease is expected to start.
One of the medications, gantenerumab, produced by Roche and its U.S. partner, Genentech, decreased amyloid levels in the brain and improved several measurements of Alzheimer’s proteins, according to Bateman and colleagues’ 2020 trial results. However, because the symptom-free group, whether receiving medication or a placebo, had not decreased, the researchers had not yet noticed any signs of cognitive gain. In order to continue examining the effects of gantenerumab and ascertain if longer treatment periods or higher dosages could prevent or postpone cognitive loss, the trial’s leaders decided to implement an open-label extension in response to the inconsistent outcomes in the symptom-free group.
Regardless of whether they had been given gantenerumab, another medication, or a placebo during the trial, all DIAN-TU participants who had a high-risk genetic mutation for Alzheimer’s disease were eligible to continue into the extension study. There was no internal control group because the experimental drug was given to every participant in the extension. Rather, the extension participants were compared to placebo-treated DIAN-TU participants who did not continue into the extension, as well as to patients in a comparable study called the DIAN Observational who had not received any pharmacological treatment.
After Roche/Genentech decided to stop developing 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 failed to meet their primary endpoint of slowing clinical decline, the three-year extension was shortened in mid-2023. By the time the extension experiment ended, the average participant had received treatment for 2.6 years.
Although the results were only statistically significant for the subgroup of individuals who began with no symptoms and received the longest treatment, analysis of this data set showed that removing brain amyloid plaques years before symptoms are expected to appear delays the onset of symptoms and the progression of dementia. There are currently no discernible impacts on cognitive function for the group of participants who got gantenerumab solely during the extension for two to three years because they were given a placebo or another medication during the first study. Gantenerumab was administered to the longest-treated group for an average of eight years, indicating that prophylaxis may require treatment years in advance of onset.
The effect was significant in the group that received treatment for the longest period of time: the chance of experiencing symptoms was reduced by half. This 50% effect size observed in the group that received gantenerumab for the longest period of time is the outcome of a calculation that accounts for both the number of individuals who experienced symptoms and the timing of symptom onset for each participant in relation to the anticipated age of onset. This implies that as time passes, the effect size may alter. A few of the participants are at or slightly past the anticipated age at which they began. The effect size will increase with the amount of time they do not have symptoms. On the other hand, some people who are currently healthy can experience symptoms later on, which would decrease the effect magnitude.
Amyloid-related imaging abnormalities, or ARIA, are a side effect associated with gantenerumab and other anti-amyloid medications. Brain scans can identify the abnormalities, which show up as localized brain swelling or microscopic blood spots in the brain. The majority of ARIA cases in clinical trials go unnoticed by participants (i.e., they don’t exhibit any symptoms) and go away on their own, but a small percentage are more severe, and in rare instances, the side effect has been connected to fatalities.
Because the researchers employed greater doses in the extension, the ARIA rates in this investigation were one-third higher than those in the original clinical trial (30% vs. 19%). Two subjects recovered after their ARIA became so bad that they had to stop using the medication. There were no fatalities or adverse events that could have been fatal. According to the researchers, gantenerumab’s safety profile in the extension was generally comparable to that of the first trial and other gantenerumab clinical trials.
With initial financing from the Alzheimer’s Association and GHR Foundation, the Knight Family DIAN-TU, based at WashU Medicine, has started the Knight Family DIAN-TU Amyloid Removal Trial to determine how long dementia can be postponed by removing amyloid. The majority of patients in the international open-label extension have begun using lecanemab, an anti-amyloid medication that was approved by the Food and Drug Administration in 2023 to reduce cognitive decline in those who already exhibit symptoms of Alzheimer’s disease, as gantenerumab was withdrawn. Analysis of the data from this extension trial phase is still pending. Researchers at WashU Medicine have applied for an NIH grant, which would finance the completion of the trial if it is accepted. The NIH is still reviewing the award.
Bateman and colleagues anticipate that the study’s findings will guide prevention and treatment initiatives for all types of Alzheimer’s disease, even though the research was restricted to those with genetic forms of the illness that cause early onset. Two decades before memory and cognitive issues appear, amyloid begins to slowly accumulate in the brain in both early-onset and late-onset Alzheimer’s disease. Furthermore, late-onset Alzheimer’s disease trials have reproduced every trial result from these early-onset Alzheimer’s mutant families.
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,
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.
Randall J. Bateman, MD
Other anti-amyloid drugs are being considered as Alzheimer’s disease prevention measures, even though gantenerumab is no longer being developed.
These exciting preliminary findings hint very clearly at the potential role of lowering beta amyloid in prevention of Alzheimer’s disease,
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.
Maria C. Carrillo
In the Primary Prevention Trial, the Knight Family DIAN-TU is assessing the experimental amyloid-removing medication remternetug, manufactured by Eli Lilly and Co. Participants in the Primary Prevention Trial are significantly younger than those in the DIAN-TU secondary prevention studies, yet they are members of families with dominant Alzheimer’s mutations. In order to find out if halting the early molecular changes that cause symptomatic Alzheimer’s disease can stop the disease from ever developing, the trial is recruiting participants as young as 18 who have few or no detectable Alzheimer’s-related molecular changes in their brains, up to 25 years before the anticipated onset of dementia symptoms.
Source: Washington University
Journal Reference: Bateman, Randall J 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.” medRxiv : the preprint server for health sciences 2024.10.29.24316289. 29 Jan. 2025, DOI: 10.1101/2024.10.29.24316289.
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Graduated from the University of Kerala with B.Sc. Botany and Biotechnology. Attained Post-Graduation in Biotechnology from the Kerala University of Fisheries and Ocean Science (KUFOS) with the third rank. Conducted various seminars and attended major Science conferences. Done 6 months of internship in ICMR – National Institute of Nutrition, Hyderabad. 5 years of tutoring experience.
