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

Anti-Aβ immunotherapies for Alzheimer's Disease (AD) have high rates of amyloid-related imaging abnormalities (ARIA), an adverse side effect with markedly higher rates in <i>APOE4</i> carriers. We developed a mouse model of ARIA centered on human <i>APOE3</i> and <i>APOE4</i> 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-Aβ immunotherapy. Across 82 mice, <i>APOE4</i> 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 <i>APOE3</i> mice. There was a concomitant significant increase in deposition of cerebral amyloid angiopathy (CAA) in <i>APOE4</i> mice at one (76%) and three (51%) days in leptomeningeal vessels. The increased CAA correlated with a significant 189% increase in Aβ within microglia of <i>APOE4</i> (but not <i>APOE3</i> ) 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 <i>APOE4</i> -specific redistribution of parenchymal amyloid to CAA by 3D6 within days, leading to increased vascular damages associated with ARIA.