By Sonja Blum, MD, PhD
Synopsis: In this open-label extension of the dominantly inherited Alzheimer’s disease gantenerumab trial (DIAN-TU), long-term continuous amyloid clearance over eight or more years in asymptomatic carriers of autosomal dominant Alzheimer’s mutations showed potential to delay symptom onset and slow progression. Shorter duration or partial clearance did not yield measurable clinical benefit, suggesting that only sustained, near-complete amyloid removal may have disease-modifying effects.
Source: Bateman RJ, Li Y, McDade EM, et al; Dominantly Inherited Alzheimer’s Disease-Trials Unit. Safety and efficacy of long-term gantenerumab treatment in dominantly inherited Alzheimer’s disease: An open-label extension of the phase 2/3 multicentre, randomized, double-blind, placebo-controlled platform DIAN-TU trial. Lancet Neurol. 2025;24(4):316-330.
The DIAN-TU study is a platform trial evaluating disease-modifying therapies in individuals with dominantly inherited Alzheimer’s disease (DIAD), who are known mutation carriers (APP, PSEN1, PSEN2) with predictable onset ages. Gantenerumab, a monoclonal antibody targeting amyloid plaques, showed partial amyloid clearance and biomarker effects in the DIAN-TU-001 Phase II/III double-blind trial but did not meet its primary cognitive endpoints.
This new study is a three-year open-label extension (OLE) of DIAN-TU-001, designed to test whether sustained, high-dose gantenerumab could fully clear amyloid plaques and prevent symptom onset. Participants received up to 1,500 mg subcutaneously every two weeks. The primary outcome was reduction in amyloid plaques (¹¹C-PiB-PET SUVR); secondary outcomes included progression on Clinical Dementia Rating (CDR), Mini-Mental State Examination (MMSE), cognitive composites, and cerebrospinal fluid (CSF) biomarkers.
A total of 73 participants entered the OLE; 55 were included in the modified intention-to-treat group. The median gantenerumab exposure was ~2.6 years in the OLE and ~8.4 years in the longest-treated subgroup. Amyloid plaque burden decreased significantly (ΔSUVR –0.71, P < 0.0001), and CSF Aβ42/40 and p-tau181/tau181 ratios normalized over time.
Crucially, although short-term or partial treatment groups (OLE-only and combined with any exposure to gantenerumab) showed no significant delay in progression, the longest-treated asymptomatic subgroup (n = 22) demonstrated a ~50% reduction in hazard for dementia progression on CDR Scale Sum of Boxes (hazard ratio, 0.53; 95% confidence interval, 0.29-0.97). These participants had achieved near-complete amyloid clearance. However, limitations include a small sample size, the use of external controls, and a lack of statistical significance in several secondary outcomes. Amyloid-related imaging abnormalities (ARIA) occurred in 53% of participants (mostly mild, asymptomatic microhemorrhages or edema), with a higher incidence at higher doses.
Commentary
This study provides the most compelling evidence to date that long-term, complete amyloid removal may delay or prevent progression to symptomatic Alzheimer’s disease in genetically at-risk individuals. Although prior anti-amyloid trials in asymptomatic individuals (e.g., A4, API) failed to show clinical benefit — possibly because of insufficient amyloid clearance or short duration — this study suggests that sustained treatment over many years may be key.1,2 Still, these results are not yet generalizable to sporadic Alzheimer’s disease. The ongoing AHEAD 3-45 trials, which are enrolling asymptomatic amyloid-positive individuals from the general population, are designed to answer this question directly, although results are not expected until 2028-2031.
Despite its limitations, the DIAN-TU gantenerumab extension study offers cautious optimism. It supports the idea that amyloid is a valid disease-modifying target if intervention begins early enough and is sustained long enough to fully remove plaques. Confirmation in broader populations is needed before prophylactic use of amyloid-clearing antibodies can be widely recommended.
Sonja Blum, MD, PhD, is Associate Professor of Clinical Neurology at Weill Cornell Medical College.
References
- Bateman RJ, Smith J, Donohue MC, et al. Two phase 3 trials of gantenerumab in early Alzheimer’s disease. N Engl J Med. 2023;389(20):1862-1876.
- Salloway S, Farlow M, McDade E, et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med. 2021;27(7):1187-1196.
In this open-label extension of the dominantly inherited Alzheimer’s disease gantenerumab trial (DIAN-TU), long-term continuous amyloid clearance over eight or more years in asymptomatic carriers of autosomal dominant Alzheimer’s mutations showed potential to delay symptom onset and slow progression. Shorter duration or partial clearance did not yield measurable clinical benefit, suggesting that only sustained, near-complete amyloid removal may have disease-modifying effects.
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