People with a rare genetic form of Alzheimer’s disease can begin to experience memory loss and dementia starting in their 30s, 40s and 50s. Although this form of the disease, known as dominantly inherited Alzheimer’s disease (DIAD), accounts for less than 1% of all Alzheimer’s disease cases, the burden on families can be devastating. Scientists have tried for years to find a way to prevent or delay the progress of DIAD. New clinical trial results are promising and may yield insights applicable to the treatment of all forms of the disease.
The Long Game
The study participants in the clinical trial were originally enrolled in the DIAN-TU trial, a large trial designed to evaluate the efficacy of anti-amyloid antibody drugs in preventing the progression of DIAD. It was launched in 2012 and recruited people from families affected by DIAD who have a mutation putting them at risk for the disease. They were symptom-free at the outset of the study. The recent research, reported in Lancet Neurology, focused on the results of a 3-year open-label extension study of DIAN-TU in which participants received gantenerumab, one of the multiple experimental antibodies used in the larger trail. Gantenerumab and other anti-amyloid antibodies attack beta-amyloid plaques, protein clumps that form in the brain due to folding errors and are believed to cause Alzheimer’s disease.
“Everyone in this study was destined to develop Alzheimer’s disease, and some of them haven’t yet,” said study co-author Randall Bateman, a professor of neurology at Washington University School of Medicine in St. Louis, Missouri. The university coordinates the Dominantly Inherited Alzheimer Network (DIAN), an international research effort.
The extension trial was halted early due to Roche’s decision to discontinue the development of gantenerumab, because large trials in patients with symptoms had shown no benefit. However, the Washington University team had a different idea. Maybe the drug could be more effective if treatment started before symptoms began. The results hint that they may be right.
In the subset of patients treated the longest—around eight years—the risk of decline dropped by half. “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,” said Bateman.
Hope and Caution
The numbers were small. Only 73 people took part in the extension, and just 22 were in the longest-treatment group. Still, experts see promise. “There is good hope that treatment of [Alzheimer’s] pathology in the preclinical stages… may be effective,” said Thomas Wisniewski of NYU Langone Health, who was not involved in the study.
The drug did what it was meant to do. After three years, amyloid levels in the brain had dropped significantly. However, gantenerumab and other anti-amyloid drugs are associated with amyloid-related imaging abnormalities (ARIAs). In the extension study, 53% of participants experienced this side effect, which was mostly mild and unnoticed. Two people had severe effects but recovered after stopping treatment. No deaths or major hemorrhages occurred.
More Trials Ahead
Gantenerumab won’t return to the market anytime soon. After Roche’s withdrawal, the drug had no clear regulatory path. But other anti-amyloid drugs, like lecanemab and donanemab, have gained approval. Some trial participants have now switched to those drugs.
Sam Gandy, associate director of the Alzheimer’s Disease Research Center at Mount Sinai, sees this study as part of a bigger picture. “We already know from the lecanemab and donanemab data that anti-amyloid antibodies (AAAs) can slow progression of common, sporadic Alzheimer’s. This paper focuses on using a different AAA to demonstrate a similar phenomenon is true in genetic early onset Alzheimer’s,” he said.
A First Step
More prevention trials are underway. Researchers are testing experimental and approved anti-amyloid drugs, hoping to see stronger results in larger groups. The recent study results, while promising, do not prove that Alzheimer’s disease can be prevented. However, they do show a path forward and offer hope for families at increased risk for the disease.
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