Intravenous anti-abeta immunotherapy acutely increases cerebral amyloid angiopathy and vascular damages in APOE4 mice

Abstract

Anti-A{beta} immunotherapies for Alzheimers Disease (AD) have high rates of amyloid-related imaging abnormalities (ARIA), an adverse side effect with markedly higher rates in APOE4 carriers. We developed a mouse model of ARIA centered on human APOE3 and APOE4 genotypes with amyloidosis (5xFAD transgene) and microglia tagged with green fluorescent protein (from the CX3CR1 promoter). We measured acute changes following a single intravenous treatment with 3D6 anti-A{beta} immunotherapy. Across 82 mice, APOE4 mice showed stepwise reductions in the number of plaques from one to ten days, with significant reductions in the subiculum (48%) and thalamus (40%) at ten days. There was no significant reduction in APOE3 mice. There was a concomitant significant increase in deposition of cerebral amyloid angiopathy (CAA) in APOE4 mice at one (76%) and three (51%) days in leptomeningeal vessels. The increased CAA correlated with a significant 189% increase in A{beta} within microglia of APOE4 (but not APOE3) mice at one day. Smooth muscle actin staining showed significant 58% reduction near CAA. MRI analysis revealed a significant 32% increase in microhemorrhages ten days following treatment. These data demonstrate an APOE4-specific redistribution of parenchymal amyloid to CAA by 3D6 within days, leading to increased vascular damages associated with ARIA.