Incidence of Amyloid-Related Imaging Abnormalities in Phase III Clinical Trials of Anti-Amyloid-β Immunotherapy

Amyloid-related imaging abnormalities (ARIA) are key safety considerations in anti-amyloid-β (Aβ) immunotherapy. ARIA can be categorized into 2 types: ARIA characterized by edema and effusion (ARIA-E) or microhemorrhages and superficial siderosis (ARIA-H). In this study, we assessed the incidence of ARIA in phase 3 randomized controlled trials (RCTs) of anti-Aβ immunotherapy and compared the incidence among different agents and APOE ε4 carrier status. PubMed and Embase databases were searched for phase 3 RCTs of anti-Aβ immunotherapy published on or before May 23, 2024. The inclusion criteria were phase 3 trials of anti-Aβ immunotherapy for mild cognitive impairment due to Alzheimer disease (AD) or mild AD dementia, with sufficient data on ARIA-E/H. The pooled incidences of ARIA and subgroup analyses according to various agents and APOE ε4 carrier status were calculated. A sensitivity analysis excluding outliers was performed. The pooled odds ratio (OR) of ARIA-E according to the APOE ε4 carrier status was also calculated. Nine phase 3 RCT cohorts from 8 eligible studies were identified, analyzing data from 6,315 patients. The pooled incidence of ARIA-E was 9.5% (95% CI 2.8%-27.3%), and the adjusted pooled incidence of ARIA-E was 25.5% (95% CI 20.4%-31.8%) in the sensitivity analysis. The pooled incidence of symptomatic ARIA-E was 6.7% (95% CI 3.5%-12.5%) and that of severe ARIA-E was 3.5% (95% CI 13.8%-8.4%). The pooled incidence of ARIA-H was 17.8% (95% CI 11.0%-27.5%), with the incidence of superficial siderosis was 9.3% (95% CI 6.1%-13.9%). The pooled incidence of isolated ARIA-H was 8.7% (95% CI 7.6%-10.1%). Subgroup analysis showed that homozygous APOE ε4 carriers had significantly higher odds of developing ARIA-E (OR 5.6, 95% CI 3.8-8.2, p < 0.001) than noncarriers. Heterozygous APOE ε4 carriers also had significantly higher odds of developing ARIA-E (OR 1.9, 95% CI 1.5-2.4, p < 0.001) than noncarriers. Although limited by small sample size and cohort-level data, our meta-analysis shows the adjusted pooled incidence of ARIA-E was 25.5% and the pooled incidence of ARIA-H was 17.8% in the recent phase 3 RCTs of anti-Aβ immunotherapy. Homozygous APOE ε4 carriers have a 5.6-fold higher risk of developing ARIA-E than noncarriers.