Mechanistic Insights into ARIA: Lessons from Mouse Models of Anti-Amyloid Immunotherapy

Monoclonal antibodies targeting amyloid-beta (Aβ), such as lecanemab and donanemab, represent a significant advancement in Alzheimer's disease (AD) therapeutics by amyloid reduction.However, these treatments are associated with amyloidrelated imaging abnormalities (ARIA), including vasogenic edema (ARIA-E) and cerebral microhemorrhages (ARIA-H).Biological mechanisms behind ARIA remain incompletely understood.Rodent models have been instrumental in elucidating ARIA pathogenesis.Transgenic lines such as 5xFAD, APP23, Tg2576, and EFAD recapitulate critical aspects of AD pathology, including Aβ deposition, cerebral amyloid angiopathy (CAA), and neuroinflammation.These models have demonstrated that factors such as APOE genotype, Fc receptor engagement, and antibody epitope specificity significantly influence ARIA susceptibility.Recent advances including spatial transcriptomics, single-cell RNA sequencing, and multiplex imaging have revealed distinct microglial phenotypes and immune signaling pathways activated during antibody-mediated Aβ clearance.Microglial activation, cytokine release, matrix metalloproteinase expression, and immune cell infiltration contribute to vascular remodeling and BBB disruption.APOE ε4 further exacerbates ARIA through impaired perivascular clearance and heightened inflammatory responses.This review highlights how preclinical models have advanced our understanding of ARIA, revealing the interplay between vascular integrity, immune activation, and genetic risk.These insights inform antibody design and treatment strategies.