Adverse Effects ARIA (ARIA-E and ARIA-H) in Aducanumab and Lecanemab According to APOE Genotype: Systematic Review of the Literature

Introduction: Alzheimer’s Disease (AD) is characterized by cerebral accumulation of β-amyloid (Aβ) plaques and tau tangles, leading to progressive cognitive decline. Monoclonal antibodies targeting Aβ, such as aducanumab and lecanemab, have demonstrated plaque reduction and slowed clinical deterioration by 25–40%, but their use is complicated by Amyloid‐Related Imaging Abnormalities (ARIA), Manifesting as Vasogenic Edema (ARIA-E) and microhemorrhages or siderosis (ARIA-H). Objective: To systematically review the incidence and characteristics of ARIA-E and ARIA-H in patients treated with aducanumab or lecanemab, stratified by APOE ε4 genotype. Methods: A systematic review of Randomized Clinical Trials (RCTs) was conducted. PubMed, Embase, Web of Science, CENTRAL, and Scopus were searched through June 2025 for RCTs reporting ARIA adverse events by APOE genotype. Trials involving adult AD or mild cognitive impairment patients with documented APOE status and imaging‐assessed ARIA were included. Data extraction and Cochrane RoB 2.0 bias assessment were performed by two independent reviewers, with narrative synthesis of ARIA incidence and management strategies. Results: Four RCTs met inclusion criteria. In phase 3 CLARITY-AD (lecanemab), overall ARIA-E incidence was 13.6%; among APOE ε4/ε4 homozygotes it rose to 34.5% versus 6.9% in non-carriers (principal result), with most cases mild/moderate and resolving within 3–6 months. Symptomatic ARIA-E occurred in 3.3% and serious events in 1.1% of all treated patients. Discussion: APOE ε4 carriage, especially homozygosity, markedly elevates ARIA risk with anti-Aβ antibodies. Pre-treatment genotyping is recommended to tailor safety monitoring: ε4/ε4 individuals may benefit from slower dose titration, more frequent MRI surveillance during the first 6–12 months, and stricter criteria for treatment interruption. These strategies aim to optimize therapeutic benefit while minimizing ARIA-related harm.