An in vivo model of Amyloid-Related Imaging Abnormalities (ARIA) predicts ARIA incidence of anti-Aβ antibodies seen in clinical trials

作者：Edward D. Plowey, Jordan Abettan, Peter Cheng Te Chou, Ming Lye-Barthel, Ana C. Amaral, Jennifer Sebalusky, Stefan Hamann, Jared Srinivasan, Roland Brown, Qian Fang, Paul Weinreb, Dominic M. Walsh, Daniel P. Bradley, Thierry Bussiere · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.01.30.702402 · 被引用次数：1 · 研究领域：Amyloidosis: Diagnosis, Treatment, Outcomes、Intracerebral and Subarachnoid Hemorrhage Research、Alzheimer's disease research and treatments

Abstract Amyloid-related imaging abnormality (ARIA) is the most common adverse event associated with amyloid-beta (Aβ) immunotherapy. The neuropathology underlying active ARIA lesions has been studied in only a few rare fatal cases. A faithful translational model of ARIA should allow a better understanding of pathogenic mechanisms and enable development of mitigation strategies. Since bapineuzumab induced the most frequent and severe forms of ARIA in humans, we assessed the ability of its murine precursor, 3D6, to induce ARIA-like lesions by applying clinically-validated MRI sequences in a mouse model with extensive amyloid deposition. Using this paradigm we documented ARIA-like changes based on their imaging features, location, and temporal evolution and established postmortem histopathologic correlates. We observed that ARIA-like lesions were ubiquitously induced with 3D6, including T2-hyperintense leptomeningeal effusions, T2-hyperintense parenchymal lesions and T2* hypointense parenchymal lesions. Histological assays demonstrated meningovascular inflammation as well as vascular mural permeation and microvascular lesions, including microhemorrhages and microinfarcts. Compared to 3D6-treated mice, animals treated with mouse analogues of aducanumab and gantenerumab showed less frequent radiologic and histopathologic ARIA-like lesions with delayed onset. Our results align well with the differential incidence of ARIA observed in humans treated with different anti-Aβ antibodies...