Apoe Immunotherapy Reduces Cerebral Amyloid Angiopathy And Amyloid Plaques While Improving Cerebrovascular Function

The epsilon 4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and greatly influences the development of amyloid-beta (A beta) pathology. Our current study investigated the potential therapeutic effects of the anti-human APOE antibody HAE-4, which selectively recognizes human APOE that is co-deposited with A beta in cerebral amyloid angiopathy (CAA) and parenchymal amyloid pathology. In addition, we tested whether HAE-4 provoked brain hemorrhages, a component of amyloid-related imaging abnormalities (ARIA). ARIA is an adverse effect secondary to treatment with anti-A beta antibodies that can occur in blood vessels with CAA. We used 5XFAD mice expressing human APOE4(+/+) (5XE4) that have prominent CAA and parenchymal plaque pathology to assess the efficacy of HAE-4 compared to an A beta antibody that removes parenchymal A beta but increases ARIA in humans. In chronically treated 5XE4 mice, HAE-4 reduced A beta deposition including CAA compared to a control antibody, whereas the anti-A beta antibody had no effect on CAA. Furthermore, the anti-A beta antibody exacerbated microhemorrhage severity, which highly correlated with reactive astrocytes surrounding CAA. In contrast, HAE-4 did not stimulate microhemorrhages and instead rescued CAA-induced cerebrovascular dysfunction in leptomeningeal arteries in vivo. HAE-4 not only reduced amyloid but also dampened reactive microglial, astrocytic, and proinflammatory-associated genes in the cortex. These results suggest that targeting APOE in the core of both CAA and plaques could ameliorate amyloid pathology while protecting cerebrovascular integrity and function.