Valentinus Besin, Farizky Martriano Humardani, Fenny Lanawati Yudiarto, Paulus Anam Ong, Sulistyo Emantoko Dwi Putra, Ratih Asmana Ningrum
Monoclonal antibodies (mAbs) have made significant progress in the treatment of Alzheimer's disease (AD). However, mAbs are associated with adverse effects, including Amyloid-Related Imaging Abnormality (ARIA), which manifests as edema or effusion (ARIA-E) and hemorrhage (ARIA-H). The mechanisms behind these effects are not yet fully understood. Moreover, spontaneous ARIA has been insufficiently explored, and mAb therapies, particularly lecanemab, have mainly focused on patients with the APOE-ε4 allele carrier. This review aims to address this gap by examining the mechanisms of spontaneous ARIA, ARIA induced by mAbs, and the influence of genetic variants on ARIA development. The autoantibody-Aβ-mediated immune response targets excessive Aβ deposits, increasing immune activity through microglial reactivity. The heightened immune response, driven by Aβ accumulation in blood vessels, promotes angiopathy and inflammation, potentially contributing to spontaneous ARIA. The APOE-ε4 allele carrier is more strongly associated with ARIA-E because it redistributes Aβ deposition from the brain to blood vessels, influencing microglial reactivity. The redistribution enhances vascular integrity and reduces the risk of ARIA-H. However, it also increases the likelihood of ARIA-E due to Aβ accumulation in the vasculature, triggering inflammation. In contrast, the development of ARIA-H is linked to increased TREM2 expression and microglial reactivity, leading to impaired vascular integrity and disrupted matrix remodeling, which worsens the condition. Additionally, the adverse effects of mAbs may extend beyond the APOE-ε4 allele, possibly impacting other genetic variants involved in microglial reactivity, Aβ redistribution, and vascular integrity. © 2025 The Author(s). Chronic Diseases and Translational Medicine published by John Wiley & Sons, Ltd on behalf of Chinese Medical Association.
Faculty of Medicine, University of Surabaya, Surabaya, Indonesia; Doctoral Program in Medical Science, Faculty of Medicine Universitas Brawijaya, Malang, Indonesia; Department of Neurology, Diponegoro University, Semarang, Indonesia; Department of Neurology, Universitas Padjadjaran, Bandung, Indonesia; Faculty of Biotechnology, University of Surabaya, Surabaya, Indonesia; Research Center for Genetic Engineering, National Research and Innovation Agency of The Republic of Indonesia (BRIN), Cibinong Sciences Center, Cibinong, Bogor, Indonesia
