An experimental medicine seems to reduce the risk of dementia related to Alzheimer’s in people aimed at developing the disease in their 30, 40 or 50 years, according to the results of a study led by the Knight Hereding family dominantly Alzheimer-Trieds (Dian-Tu), which is based on the University of Washington Medicine in St. Louis. The findings suggest, for the first time in a clinical trial, that early treatment to eliminate amyloid plates from the brain many years before the symptoms arise can delay the appearance of Alzheimer’s dementia.
The study is published on March 19 in Lanceta neurology.
The international study involved 73 people with rare and hereditary genetic mutations that cause amyloid overproduction in the brain, almost guaranteeing that they will develop Alzheimer’s disease in the middle age. For a subgroup of 22 participants who did not have cognitive problems at the beginning of the study and who received the longest medication, an average of eight years, the treatment reduced the risk of developing symptoms essentially from 100% to 50%, according to a primary analysis of the data and supported by multiple sensitivity analysis that support the trend.
“All in this study were destined to develop Alzheimer’s disease and some of them have not yet done so,” said Senior Author Randall J. Bateman, MD, Charles F. and Joanne Knight distinguished neurology professor at Washu Medicine. “We still do not know how long they will remain free of symptoms, perhaps a few years or maybe decades. To give them the best opportunity to stay cognitively normal, we have continued the treatment with another anti-amyloid antibody in the hope that they will never develop symptoms at all. What we know is that it is possible to at least delay the beginning of the symptoms of Alzheimer’s disease and give the most healthy people.” “.” “.” “
The findings provide new tests to support the so -called amyloid hypothesis of Alzheimer’s disease, which postulates that the first step on the road to dementia is the accumulation of amyloid plaques in the brain, and that eliminating such plaques or blocking its formation can prevent the symptoms from arising. For this study, Bateman and his colleagues evaluated the effects of an experimental anti-amyloid medication to see if the medicine could prevent the development of dementia.
The study population was formed by people who had originally registered in the Knight Dian-Tu-001 family, Alzheimer’s first prevention trial in the world, and then continued in an extension of the essay in which they received an anti-amyloid medicine. Currently led by Bateman and mainly financed by the Alzheimer’s Association, the GHR Foundation and the National Institutes of Health (NIH), the Caballero Dian-Tu-001 family was launched in 2012 to evaluate anti-amyloid medications as preventive therapies for Alzheimer’s disease. All trial participants did not have a very mild cognitive decrease, and were within 15 years prior to 10 years after their expected age of Alzheimer’s start, depending on family history.
When the trial concluded in 2020, Bateman and his colleagues reported that one of the drugs, Gantenerumab, made by Roche and his American subsidiary, Genentech, reduced amyloid levels in the brain and improved some measures of Alzheimer’s proteins. But researchers still did not see evidence of cognitive benefit because the group without symptoms, regardless of whether they were taking drug or placebo, had not decreased. These mixed results in the group without symptoms led the leaders of the trial to launch an open extension so that researchers could continue studying the effects of Gantenerumab and determine whether higher doses or a longer treatment could prevent or delay cognitive decrease.
All Dian-Tu participants who carried a high-risk Alzheimer’s genetic mutation were eligible to continue in the extension study, regardless of whether they had received Gantenerumab, another medicine or a placebo during the trial. Because all participants in the extension received the experimental medicine, there was no internal control group. On the other hand, the researchers compared the participants of the extension with the people in a study related as Dian Observational that had not received drug treatment, and with the participants of DIAN-TU with placebo treated that did not continue in the extension.
Originally planned for three years, the extension was reduced in mid -2023 after the decision of Roche/Genentech of discontinuating the development of Gantenerumab in November 2022 after the data of its crucial phase of phase 3 graduates I and II II that evaluate the ganteneneumab in people with early Alzheimer’s disease did not fulfill its primary end point to decelerate the decline clinical clinical clinical. The average participant in the extension trial had been treated for 2.6 years at the time it was finished.
The analysis of this data set revealed that the elimination of cerebral amyloid plaques years before the symptoms are expected to arise in the beginning of the symptoms and the progression of dementia, although the results were only statistically significant for the subgroup of people who began without symptoms and were treated longer. For the group of participants who received Gantenerumab only during the extension for two or three years because they had received another medicine or placebo during the original essay, there have not yet observable effects on cognitive function. The oldest group had received Gantenerumab for eight years on average, which suggests that the treatment years before the beginning may be necessary for prevention.
In the longest group, the effect was strong: treatment reduces the risk of developing symptoms in half. This 50% effect size seen in the group treated with a longer Gantenerumab is the result of a calculation that takes into account not only how many people developed symptoms, but also when symptoms for each participant emerged compared to their expected age of start. That means the effect size could change as time passes. Some of the participants are or only after their expected age. The longer they spend without developing symptoms, the greater the effect size will be. On the contrary, some who are healthy can now develop symptoms in the future, reducing effect size.
Gantenerumab and other anti-amyloid medications have been related to a side effect known as abnormalities of amyloid-related images, or Aryan. The abnormalities are detectable in brain scan and represent small blood spots on the brain or localized swelling of the brain. In clinical trials, most Aria cases are not noticed by participants (that is, they do not show symptoms) and are resolved on their own, but a minority is more serious and, rarely, deaths have been related to the side effect. In this study, Aria’s rates were a third higher than in the original clinical trial (30% compared to 19%), which researchers attribute to the highest doses used in the extension. Two participants developed such a serious ARIA that they needed to be taken from the medicine, at which time they recovered. There were no potentially mortal adverse events or deaths. In general, Gantenerumab’s security profile in the extension was similar to that of the original trial and in other clinical trials of Gantenerumab, the researchers said.
To answer the question of how long the dementia can be delayed eliminating the amyloid, the Caballero Dian-Tu family, based in Washu Medicine, has launched the amyloid elimination judgment of the Knight Dian-Tu family, with initial funds of the Alzheimer’s association. Because the Gantenerumab was suspended, the majority of participants in the open international extension have begun to receive Lecanemab, an anti-amyloid medicine approved by the Food and Drug Administration in 2023 to slow down the cognitive decrease of people who already have symptoms of Alzheimer’s disease. The data in this phase of the extension test have not yet been analyzed. Washu medicine researchers have presented a NIH subsidy that, if approved, would provide funds to finish the trial. That subsidy is still pending NIH review.
While the essay was limited to people with genetic forms of Alzheimer’s that lead to early onset, Bateman and his colleagues expect the results of the study to inform prevention and treatment efforts for all forms of Alzheimer’s disease. Alzheimer’s disease early and late onset begins with the collection of amyloid slowly in the brain two decades before memory and thought problems. In addition, all the results of the essay of these families of mutation of Alzheimer’s early onset have been replicated in the latest Alzheimer’s disease tests.
“If Alzheimer’s prevention trials of late onset have similar results with Dian-Tu tests, there could be Alzheimer’s preventions available for the general population,” Bateman said. “Now I am very optimistic, since this could be the first clinical evidence of what will become preventions for people at risk of Alzheimer’s disease. One day soon, we can delay the beginning of Alzheimer’s disease for millions.”
Although the Gantenerumab is no longer being developed, other anti-amyloid medications are evaluated such as preventive medications for Alzheimer’s disease.
“These exciting preliminary findings suggest very clearly the potential role to reduce beta amyloid in the prevention of Alzheimer’s disease,” said Maria C. Carrillo, PHD, director of scientists of the Alzheimer’s Association and leader of medical affairs. “The Alzheimer Association awaits with great anticipation of the replication, extension and expansion of this genuinely unprecedented and innovative research, and we have made a significant investment to ensure that these important scientific questions can be investigated. Discoveries such as this illustrated convincingly why it is so important for Alzheimer’s research and all diseases that cause dementia, expand and accessories,” “.
The Knight Dian-Tu family is evaluating the investigation of medicines that resort to amyloids, made by Eli Lilly and Co., in the Primary Prevention Test. Like Dian-Tu Secondary Prevention Essays, the primary prevention trial involves members of families who carry dominant Alzheimer’s mutations, but primary prevention participants are much younger. The essay is enrolling people of only 18 who have few or no alzheimer’s change detectable in their brains, up to 25 years before the expected start of dementia symptoms, to determine whether to stop early molecular changes that lead to symptomatic Alzheimer’s disease can prevent the disease from taking over.
The part of DIAN-TU-001 of this study was financed by subsidies from the National Institute of Aging of the National Health Institutes (U01AG042791, U01AG042791-S1 (FNIH and accelerated medicines), R01AG046179, R01AG053267, R01AG0533333267 S1 and 1 and 1 and 1 and 1 1 and 1 Y Y Y R01AG YY R01AG053267 R01AG053267-S2); The Alzheimer Association; Eli Lilly and Company; F. Hoffman-Alaroche Ltd.; Avid Radiopharmaceuticals (a total property subsidiary of Eli Lilly and Company); GHR Foundation; an anonymous organization; Cerveau technologies; Cogstate and signer. The Dian-Tu has also received funds from the Dian-Tu Pharma consortium. The extension of the Gantenerumab open label was supported by the Alzheimer’s Association and F. Hoffman-LTD.