Influence of microglial cell depletion and repopulation on aducanumab induced ARIA and vascular lesions in APOE4 carriers with AD

After many failed clinical trials, the FDA recently approved new breakthrough antibody therapy for use in early AD. But these

therapies have been revealed to increase the frequency of amyloid-related imaging abnormalities (ARIAs). Importantly, ARIA occurs more frequently in APOE4 carriers. Although the mechanism is unclear, ARIA is thought to occur after removal of

amyloid from blood vessels with cerebral amyloid antipathy (CAA). APOE4 allele is one of the strongest risk factors for AD and has been shown to promote cerebrovascular lesions such as CAA and microhemorrhages. Because CAA is universally observed in AD, further investigation of APOE4-dependent mechanisms driving CAA and ARIA-events is needed. Activated microglia

have been shown to drive the outcome and pace of APOE-mediated neurodegeneration. Importantly, microglia can modulate

cerebrovascular integrity and cerebral blood flow, and release factors which contribute to BBB breakdown, cerebrovascular cell

damage and neurovascular injury. In our studies, we revealed an increase in inflammatory pathways in AD vs control human

cerebrovessels, and this was more prominent in APOE4 carriers, who also had higher CAA scores. Anti-Aβ antibody related ARIA has also been associated with reactive microgliosis in a primate model of CAA. In humans, in vivo PET imaging of

microglial activation has been associated with the magnitude and severity of ARIA. No preclinical models have evaluated this

association between activated microglia response and ARIA-events, particularly in the context of APOE4 genotype. In this

proposal, we will address these unknowns by utilizing microglial ablation and repopulation techniques in a previously described chronic anti-Aβ treated EFAD mouse model of AD expressing human APOE isoforms and AD mutations (i.e., aducanumab

treated E3FAD and E4FAD mice). From these studies, we will generate a detailed time-course of cognitive function, cerebral blood flow and cerebrovascular reactivity, and characterize the histopathological and biochemical level changes to the

cerebrovasculature. No studies have characterized the cerebrovascular cell phenotypes in ARIA patients. We will thus employ a

single cell transcriptomic approach to characterize the phenotypic brain vascular cell type response(s) in our EFAD models following aducanumab treatment with/without macrophage depletion and repopulation, and reveal key upstream regulators

driving these unique vascular cell responses at the single cell level. From this proposal, our goal is to reveal whether activated microglia mediated cerebrovascular inflammation contributes to APOE4 mediated ARIA events following aducanumab

treatment, and ii) identify novel targets through which APOE4 confers these vascular-specific abnormalities, to reveal new

opportunities for improved antibodies and adjunct therapies that can one day minimize these complications in APOE4 patients with AD.