Early Amyloid Plaque Removal May Delay Alzheimer Disease Onset, A First-of-Its-Kind Study Suggests
In a small study of adults genetically predisposed to early-onset dementia, anti-amyloid treatment to remove plaque reduced risk of developing symptoms by 50%.
An experimental anti-amyloid drug may significantly delay the onset of Alzheimer disease in individuals genetically predisposed to develop early-onset dementia, according to new findings from an international study led by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) at Washington University School of Medicine in St. Louis. 1
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The trial revealed that among a small group of participants who received the investigational anti-amyloid drug gantenerumab for an average of 8 years, the risk of developing Alzheimer's symptoms was reduced from nearly 100% to approximately 50%.1
The findings suggest that removal of amyloid plaque from the brain many years before symptoms begin may delay the onset of Alzheimer dementia, according to the study authors, led by Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished professor of neurology at WashU Medicine.1
The study, published in The Lancet Neurology, examined 73 asymptomatic adults with dominantly inherited Alzheimer's disease (DIAD) mutations, a rare gene expression that “all but guarantees” onset of Alzheimer disease in middle age. Participants were treated with gantenerumab in either the double-blind or high-dose open-label extension phase of the ongoing DIAN-TU-001 trial.1
FINDINGS
Analysis of clinical decline using the Clinical Dementia Rating-Sum of Boxes showed a hazard ratio of 0.79 (95% CI 0.47 to 1.32) for asymptomatic DIAD participants treated with gantenerumab at any stage of the study. For the 22 participants who received gantenerumab for the longest period, a mean of 8 years, the HR for clinical decline was 0.53 (95% CI 0.27 to 1.03).1 The findings derive from a primary data analysis and are supported by several sensitivity analyses, according to a WashU Medicine statement.2
Analysis by Bateman and colleagues after a median of 2.6 years showed the adjusted mean change in amyloid plaque levels, as measured by standardized uptake value ratio (SUVR) on amyloid PET scan, was -0.71 (95% CI -0.88 to -0.53, P <.001), a confirmation of significant amyloid reduction, the authors wrote.1
The researchers reported amyloid-related imaging abnormalities (ARIA) in 53% of participants. Of these, 47% experienced microhemorrhages, 30% developed edema, and 6% had superficial siderosis. Most ARIA were asymptomatic and there were no observed macrohemorrhages. There were no fatalities during the study and only 2 participants discontinued.1
Although the clinical dementia findings fell short of statistical significance, they still mark the first potential evidence in a clinical trial that early plaque reduction during asymptomatic disease may impact Alzheimer onset and progression.
“Everyone in this study was destined to develop Alzheimer’s disease, and some of them haven’t yet,” Bateman said in the WashU Medicine statement. “We don’t yet know how long they will remain symptom-free—maybe a few years or maybe decades. What we do know is that it’s possible to delay the onset of the symptoms of Alzheimer’s disease and give people more years of healthy life.”2
“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. What we do know is that it’s possible to delay the onset of the symptoms of Alzheimer’s disease and give people more years of healthy life.”
The double-blind portion of the DIAN-TU trial of gantenerumab finished in 2019 and did not meet its primary endpoint of slowing cognitive decline. In that phase there were 144 participants with 52 receiving the study drug. A subsequent open label extension was terminated early based on the failure of gantenerumab to reduce or retard disease program in participants with symptomatic Alzheimer disease, according to the statement.2
Participants in the double-blind phase 2/3 DIAN-TU trial were assessed as either cognitively normal or with mild dementia and were within 15 years before or a decade after their expected age of Alzheimer onset based on family history, according to the study.1
The DIAN-TU program has initiated new trials to assess alternative amyloid-removing drugs. And while gantenerumab is no longer in clinical development, the majority of participants from the open label phase have initiated lecanemab (Leqembi; Eisai/Biogen).2
“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,” Bateman said. “One day soon, we may be delaying the onset of Alzheimer’s disease for millions.”2
