A SECONDARY analysis of the TRAILBLAZER-ALZ 2 trial has revealed that reduced posttreatment amyloid burden following donanemab administration is strongly correlated with slower clinical decline, reinforcing the therapeutic promise of donanemab as an Alzheimer’s treatment.
Amyloid Burden and Disease Mechanisms
Amyloid plaque accumulation remains central to the progression of Alzheimer disease. Therapies that target amyloid clearance, such as donanemab, are reshaping the landscape of Alzheimer’s treatment by addressing disease mechanisms directly. This analysis aimed to determine whether reductions in posttreatment amyloid burden could translate into tangible cognitive and functional benefits for patients with early symptomatic disease.
Secondary Trial Analysis Confirms Clinical Benefits
Researchers evaluated data from 1582 participants enrolled in the phase 3, placebo-controlled TRAILBLAZER-ALZ 2 trial, conducted across 277 centres in eight countries between June 2020 and April 2023. Participants, aged 60 to 85 years, received either donanemab or placebo every four weeks for up to 72 weeks. Those receiving donanemab showed substantially lower posttreatment amyloid levels than the placebo group.
Lower posttreatment amyloid levels correlated with slower decline in cognitive function as measured by the integrated Alzheimer’s Disease Rating Scale (R² = 0.73, 95% CI 0.37–0.97) and Clinical Dementia Rating–Sum of Boxes (R² = 0.87, 95% CI 0.70–0.97). Reductions were also associated with improved plasma biomarkers, including phosphorylated tau 217 (R² = 0.86) and glial fibrillary acidic protein (R² = 0.87), strengthening evidence that plaque removal underpins Alzheimer’s treatment efficacy.
Implications for Future Alzheimer’s Treatment
The findings support amyloid plaque removal as a central mechanism of action for donanemab and validate posttreatment amyloid levels as a potential biomarker for clinical response. As the search for more effective Alzheimer’s treatment continues, these results may guide targeted therapies and improve early disease management in future clinical practice.
Reference
Lu M et al. Posttreatment amyloid levels and clinical outcomes following donanemab for early symptomatic alzheimer disease: a secondary analysis of the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA Neurol. 2025;DOI:10.1001/jamaneurol.2025.3869.
