AT the 2025 American Academy of Neurology (AAN) Annual Meeting in San Diego, new data from the TRAILBLAZER-ALZ clinical trial program highlighted critical risk factors and management strategies for amyloid-related imaging abnormalities (ARIA) in patients with early symptomatic Alzheimer’s disease treated with donanemab. ARIA, which includes cerebral edema (ARIA-E) and hemorrhages (ARIA-H), remains a significant safety concern associated with amyloid-targeting therapies (ATTs).
Researchers presented an integrated analysis of ARIA incidence and severity across several donanemab trials: TRAILBLAZER-ALZ, TRAILBLAZER-ALZ 2, and TRAILBLAZER-ALZ 6, incorporating a total of 1983 participants for standard dosing data and 843 participants for dosing comparisons. Standard treatment involved a titration period of 700 mg doses every 4 weeks, followed by 1400 mg every 4 weeks.
In the combined datasets from TRAILBLAZER-ALZ and TRAILBLAZER-ALZ 2, ARIA-E occurred in 24.4% and ARIA-H in 31.3% of donanemab-treated patients. Most ARIA-E events were radiographically mild to moderate (90.7%) and asymptomatic (76.3%). The number of APOE ε4 alleles and the presence of cortical superficial siderosis were linked to a higher risk of developing ARIA.
The TRAILBLAZER-ALZ 6 trial tested alternative dosing regimens. A modified titration arm showed significantly reduced ARIA-E rates, 13.7% compared to 23.7% at 24 weeks, while maintaining similar amyloid plaque reduction and cumulative drug exposure compared to the standard regimen.
Additionally, enhanced MRI protocols were evaluated. Susceptibility-weighted imaging (SWI), used alongside traditional T2*-weighted GRE scans, provided greater sensitivity. When SWI-based scans were analyzed using T2*GRE-based criteria, only 4.5% of participants would have been excluded, indicating SWI’s potential role in risk stratification.
These findings suggest that adjusting dosing strategies and incorporating advanced imaging and genetic screening may help mitigate ARIA risk in clinical practice.
Reference: Biffi A et al. ARIA Risk Factors and Management Experience in Donanemab Clinical Trials in Early Symptomatic Alzheimer’s Disease. 2025 American Academy of Neurology (AAN) Annual Meeting, April 5-9, 2025, San Diego, California, USA.
