According to an open-label study from Washington University in St. Louis, the anti-amyloid drug gantenerumab reduced the risk of developing familial Alzheimer’s disease in a subgroup of participants [1].
Is it about amyloid beta?
Despite billions of dollars invested in developing therapies against Alzheimer’s disease, the progress has been slow. The decades-old amyloid cascade hypothesis postulates that plaques of the insoluble peptide amyloid beta in the brain, first noticed by Alois Alzheimer himself more than a century ago, are the main culprit. The researchers learned to effectively clear those plaques, but this didn’t lead to a revolution in Alzheimer’s treatment. For instance, the recently approved state-of-the-art drug leqanemab (Leqembi) is only able to moderately slow the disease’s progression, despite being effective in removing the plaques.
As these successes are so modest, the amyloid hypothesis comes into question: after all, if amyloid plaques are the main cause, their removal should lead to the reversal of symptoms. The hypothesis’ advocates counter that interventions might occur too late, when the cascade of deterioration, which also includes the accumulation of tau-protein tangles inside brain cells, is already well underway.
Unfortunately, showing that anti-amyloid drugs can prevent Alzheimer’s rather than slow its advance is a massive multi-year undertaking. Treatment must start early in a big sample of healthy people and show that fewer of them eventually develop Alzheimer’s than those without the treatment. Such long-term trials have been largely unsuccessful – at least until now.
A tale of two studies
A paper published in Lancet Neurology presents data from a trial of the anti-amyloid drug gantenerumab. This trial focused on the dominantly inherited Alzheimer’s disease (DIAD), which is associated with certain genetic variants. People with DIAD have a very high risk of getting Alzheimer’s in their 30s to 50s. While the familial version of the disease is not similar to sporadic Alzheimer’s, working with the former simplifies things.
The study was an open-label extension (OLE) of a larger study, DIAN-TU-001, the world’s first Alzheimer’s prevention trial. That study ran between the years 2012 and 2019, and gantenerumab failed to impress. OLE is when participants in the original study, including the placebo arm, are invited to continue (or start) taking the drug, sometimes at different regimens.
OLEs are not blinded, as the participants know they’re taking the drug; they are not randomized, as participant selection is not random and is skewed towards those who didn’t drop out of the original study; and they are not controlled, as there is no control group. OLEs are conducted to gather additional safety or efficacy data about the drug, but their drawbacks make them less valuable than randomized controlled trials (RCTs).
In 2023, the drug’s sponsor, pharma giant Roche, gave up on gantenerumab. Since then, the researchers have been crunching OLE data and now released the results. The study goes on, but due to the discontinuation of gantenerumab, most participants are now receiving lecanemab. However, finishing this new part of the study requires more funds, and the grant is now under review by NIH.
Risk reduction in a small subgroup
Among the 73 participants in the open-label study, the researchers claim to have detected a statistically significant effect on the risk of developing Alzheimer’s in a subgroup of 22. Those were people who had little to no symptoms prior to their enrollment in the original study and took the drug for the longest period of time (eight years on average). According to the authors’ calculations, the risk of developing the disease in this subgroup was slashed by half by the treatment.
Since the study lacked a control group, scientists pitted the results against those from a comparable group of participants in the placebo arm of the original study and in a sister study, DIAN Observational. The researchers controlled for the expected age of onset derived from the participants’ familial history of Alzheimer’s.
“Everyone in this study was destined to develop Alzheimer’s disease, and some of them haven’t yet,” said senior author Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology at WashU Medicine. “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.”
Glass half empty
Not all researchers sounded as excited. Dr. Sebastian Walsh, NIHR Doctoral Fellow in Public Health Medicine, University of Cambridge, who was not involved in this study, said: “The results of this very small trial are actually ’null’ – meaning there is no strong evidence of a positive finding. A more accurate interpretation of the findings would be that this drug, like several other drugs before, demonstrated its effectiveness at removing the amyloid protein from the brain. But there was no convincing evidence in this trial that this led to any actual benefit for the participants in terms of the development or worsening of dementia symptoms. This is either because the effects were too small, or the study was too small, or a combination of both.”
Walsh cited several additional limitations of the study, including the fact that it was not blind and that familial Alzheimer’s differs from the sporadic form of the disease: “Evidence from population studies tells us that we cannot assume that findings from groups like this will translate to the majority of people who develop clinical Alzheimer’s disease – who often have other things going wrong in their brain, beyond the amyloid protein being targeted in this study, and typically also have other medical conditions affecting the rest of the body. These people are mostly older, frailer, and more complex.”
Bateman, however, is keeping his spirits up. “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,” he 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.”
Literature
[1] Bateman, R. J., Li, Y., McDade, E. M., Llibre-Guerra, J. J., Clifford, D. B., Atri, A., … & Schofield, P. R. (2025). 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, 24(4), 316-330.
