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.

Automated summary

The study examined the therapeutic effects of the anti-human APOE antibody HAE-4 in reducing amyloid pathology and protecting cerebrovascular integrity. Compared to other anti-Aβ antibodies, HAE-4 did not induce microhemorrhages and improved the function of brain arteries.