Comparative risk of amyloid-related imaging abnormalities with anti-amyloid-β monoclonal antibodies: A systematic review and penalized likelihood network meta-analysis of randomized trials.

BackgroundAnti-amyloid-β monoclonal antibodies represent a new class of disease-modifying therapies for Alzheimer's disease (AD). Their clinical adoption is complicated by amyloid-related imaging abnormalities (ARIA), encompassing vasogenic edema (ARIA-E) and hemorrhagic changes (ARIA-H). The comparative ARIA risk across agents and the influence of genetic factors remain incompletely characterized.ObjectiveTo quantify the pooled incidence of ARIA-E and ARIA-H associated with anti-amyloid-β immunotherapies and to compare relative risks across agents using network meta-analytic modeling.MethodsFollowing PRISMA guidelines (PROSPERO: CRD420250653157), we searched PubMed, EMBASE, Scopus, Web of Science, and Ovid through January 2026 for Phase II/III randomized controlled trials of anti-amyloid-β immunotherapies in AD. Random-effects models estimated pooled prevalence and odds ratios (ORs). A penalized likelihood network meta-analysis addressed sparse events. APOE ε4-stratified analyses and Bayesian sensitivity models were also performed.ResultsTwenty-two trials (up to 23,120 participants) were included. Pooled ARIA-E prevalence was 6.8% and ARIA-H was 15.8%, with substantial heterogeneity. Anti-amyloid-β therapy significantly increased odds of ARIA-E (OR 7.93; 95% CI 4.50-13.98) and ARIA-H (OR 1.87; 95% CI 1.28-2.72) versus placebo. The highest ARIA-E risk was seen with donanemab and aducanumab, followed by gantenerumab and lecanemab. APOE ε4 carriage significantly elevated ARIA-E (OR 2.28) and ARIA-H (OR 2.07) risk, with a clear gene-dose effect in homozygotes.ConclusionsARIA risk varies substantially across anti-amyloid-β therapies and is strongly modulated by APOE ε4 status. These findings support genotype-informed risk stratification and individualized MRI monitoring to optimize the benefit-risk balance of disease-modifying therapies in AD.