Removing amyloid appeared to delay Alzheimer's symptoms in asymptomatic patients.
Participants in this study are genetically destined to develop Alzheimer's at predictable ages.
The findings were the first to hint that treating asymptomatic Alzheimer's disease might reduce progression.
Long-term removal of amyloid beta in people genetically destined to develop Alzheimer's disease may have delayed symptoms and disease progression, data from the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) suggested.
Among 53 asymptomatic people with dominantly inherited Alzheimer's disease who were treated with investigational gantenerumab in either the double-blind portion or open-label extension of a DIAN-TU study, the hazard ratio (HR) for clinical decline based on Clinical Dementia Rating-Sum of Boxes scores was 0.79 (95% CI 0.47-1.32), reported Randall Bateman, MD, of Washington University School of Medicine in St. Louis, and co-authors.
For a subgroup of 22 people who received gantenerumab the longest -- an average of 8 years -- the HR for clinical decline was 0.53 (95% CI 0.27-1.03), they noted in Lancet Neurology.
After a median 2.6 years of treatment, the adjusted mean change in standardized uptake value ratio (SUVR) on amyloid PET was -0.71 (95% CI -0.88 to -0.53, P<0.0001). Amyloid-related imaging abnormalities (ARIA) occurred in 53% of participants; most were asymptomatic. No treatment-associated macrohemorrhages or deaths occurred.
While the clinical dementia findings did not reach statistical significance, they were the first to provide a hint that early treatment and amyloid plaque removal in asymptomatic Alzheimer's disease might delay symptoms and reduce the risk of progression, the researchers said.
"Everyone in this study was destined to develop Alzheimer's disease and some of them haven't yet," Bateman said in a statement.
"We don't yet know how long they will remain symptom-free -- maybe a few years or maybe decades," he added. "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."
The ongoing DIAN-TU platform tests the safety and effectiveness of investigational drugs in people at risk of developing Alzheimer's due to autosomal dominant mutations in PSEN1, PSEN2, or APP genes. These individuals develop cognitive symptoms at relatively predictable ages, depending on the mutation they carry and their family history.
The double-blind portion of the DIAN-TU gantenerumab trial included 144 participants, with 52 on active treatment. It finished in 2019 and did not meet its primary endpoint of slowing cognitive decline. An open-label extension started a year later but was stopped prematurely after other trials of gantenerumab failed in people with symptomatic Alzheimer's disease.
This analysis of DIAN-TU gantenerumab extension data highlights the feasibility of prolonged treatment trials in asymptomatic familial Alzheimer's disease, observed Jonathan Schott, MD, of University College London.
In an accompanying editorial, Schott noted that "as has been the case with many previous Alzheimer's disease trials, there is much to be learned from incomplete, prematurely terminated, or open-label studies."
The suggestion of disease-slowing seen in this analysis justifies both ongoing follow-up "to confirm whether early amyloid-beta clearance does meaningfully delay time to cognitive decline, and future studies using more effective drugs targeting amyloid-beta in DIAN-TU and other asymptomatic familial Alzheimer's disease cohorts," Schott added.
All participants in the double-blind DIAN-TU gantenerumab trial were cognitively normal or had mild dementia and were within 15 years before to 10 years after their expected age of Alzheimer's onset based on family history.
Of 74 participants recruited into the open-label extension, 73 were enrolled and received gantenerumab treatment. A total of 53 people who were asymptomatic at baseline were included in the clinical dementia rating analysis.
Because gantenerumab is no longer being developed, most participants in the open-label extension have started receiving lecanemab (Leqembi), an anti-amyloid drug approved for early symptomatic Alzheimer's disease. Data from this phase of the extension trial have not been analyzed.
The researchers have submitted an NIH grant application that, if approved, would provide funding to finish the trial. That grant is pending NIH review.
Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow
Disclosures
DIAN-TU is supported by the National Institute on Aging, the Alzheimer's Association, Eli Lilly and Company, F. Hoffmann-La Roche, Avid Radiopharmaceuticals, the GHR Foundation, Cerveau Technologies, Cogstate, Signant, and the DIAN-TU Pharma Consortium.
The gantenerumab open-label extension was supported by the Alzheimer's Association and F. Hoffmann-La Roche.
Bateman is director of DIAN-TU and reported extensive relationships with industry, including the study funders. Co-authors also reported extensive relationships with industry.
Schott reported relationships with the National Institute for Health Research UCL Hospitals Biomedical Research Centre, Alzheimer's Association, Alzheimer's Research UK, the UK Medical Research Council, the LifeArc Foundation, the British Heart Foundation, Oxford University Press, Henry Stewart Talks, Eli Lilly, Roche, Biogen, and the American Academy of Neurology.
Primary Source
Lancet Neurology
Source Reference: Bateman RJ, 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" Lancet Neurol 2025; DOI: 10.1016/S1474-4422(25)00024-9.
Secondary Source
Lancet Neurology
Source Reference: Schott JM "Amyloid immunotherapy to prevent Alzheimer's disease: the wrong drug at the right time?" Lancet Neurol 2025; DOI: 10.1016/S1474-4422(25)00066-3.