ARIA Risk in Anti-Amyloid Therapy Tied to ApoE4 and DosageRisk Factors Linked to Side Effects in Alzheimer's Treatments

BACKGROUND: Amyloid-related imaging abnormalities (ARIA) are the most concerning side effect of the treatment for early Alzheimer's disease (AD) with anti-amyloid monoclonal antibodies (mAbs). OBJECTIVE: This study systematically evaluates the incidence, severity, and associated risk factors of ARIA in patients with early AD receiving anti-amyloid mAbs therapy. METHODS: A comprehensive systematic review and meta-analysis were conducted following PRISMA guidelines. Assessed outcomes included ARIA incidence, symptomatic cases and severity, radiographic severity, and risk factors. Pooled incidences and odds ratios were estimated with a random effects model using the R software (version 4.5.2). RESULTS: The systematic search yielded a total of 20 articles, representing 21 phase 3 randomized controlled trials that involved 12,610 AD patients. Pooled incidence was 5.4% for ARIA-E and 10.27% for ARIA-H. Most cases being asymptomatic and radiographically mild to moderate. Risk factor analysis revealed that ApoE 4 homozygotes carriers (OR = 5.12), ApoE 4 heterozygotes carriers (OR = 1.91), higher mAb dosage (OR = 2.0) and baseline microhemorrhages (OR = 1.43) had a major influence on ARIA-E occurrence, as for ARIA-H incidence was higher in ApoE 4 heterozygous (OR = 1.65) and homozygotes carriers (OR = 4.65). Moreover, ApoE 4 heterozygous and homozygotic carriers were associated with symptomatic (OR = 1.52;3.68) and severe radiographic (OR = 2.11;6.31) ARIA-E. DISCUSSION: ARIA remains a significant safety concern in anti-amyloid mAb therapy, with incidence and severity influenced by genetic, neuroimaging, and treatment-related factors. Future research should focus on refining risk stratification and understanding long-term consequences of ARIA.