DONANEMAB TREATMENT significantly increases the risk of amyloid-related imaging abnormalities (ARIA) in early symptomatic Alzheimer’s disease, with most events occurring within the first three months of therapy, according to a secondary analysis of the TRAILBLAZER-ALZ and ALZ 2 trials.
Alzheimer’s disease treatments targeting amyloid plaques, such as the monoclonal antibody donanemab, are associated with ARIA—a spectrum of MRI-detected adverse events including cerebral edema (ARIA-E) and microhemorrhages (ARIA-H). This secondary analysis of 3,030 participants from two placebo-controlled trials and one open-label addendum aimed to characterise ARIA frequency, severity, timing, and risk factors, critical for optimising patient safety in clinical practice.
The study included 984 donanemab-treated and 999 placebo participants across controlled trials, plus 1,047 in an open-label extension. Donanemab increased ARIA-E incidence to 24.4% (vs 1.9% placebo) and ARIA-H to 31.3% (vs 13.0%), with similar rates in the open-label cohort (19.8% ARIA-E, 27.2% ARIA-H). Most ARIA-E cases were mild/moderate (94.2% asymptomatic), but 1.5% were serious and 5.8% symptomatic, typically presenting as headache or confusion. Notably, 58.3% of ARIA-E events arose within the first three infusions. Risk factors included APOE ε4 allele dose (OR=2.1–3.5 per allele), baseline microhemorrhages, cortical superficial siderosis, elevated amyloid burden, and higher mean arterial pressure, while antihypertensive use reduced risk.
These findings highlight the necessity of rigorous MRI monitoring, particularly early in treatment and for APOE ε4 carriers. Clinicians should prioritise baseline neuroimaging and genetic screening to stratify ARIA risk. Future research must refine predictive models and explore mitigation strategies, such as antihypertensive protocols, while balancing donanemab’s efficacy (35% slower cognitive decline) against its safety profile. Regulatory bodies and hospitals should standardise monitoring frameworks to enable safer adoption of amyloid-targeting therapies in diverse care settings.
Reference
Zimmer JA et al. Amyloid-related imaging abnormalities with donanemab in early symptomatic alzheimer disease: secondary analysis of the TRAILBLAZER-ALZ and ALZ 2 randomized clinical trials. JAMA Neurol. 2025;DOI:10.1001/jamaneurol.2025.0065.
