Abstract Recent positive results in patients passively immunized with anti-Aβ monoclonal antibodies, such as aducanumab , lecanemab, and donanemab are encouraging. Unfortunately, the incidence of adverse Amyloid Imaging Related Abnormalities (ARIA-E and -H) in response Aβ immunotherapy has been alarming. Thus, there is renewed interest in understanding the cellular and molecular mechanisms that can be targeted to protect the blood-brain barrier (BBB), during therapeutic interventions that target Aβ. We propose to rigorously investigate the underlying adverse brain blood vessel responses to passive anti-Aβ immunotherapy that result in ARIAs, and other potentially adverse cerebrovascular responses. We previously published on a symptomatic case of ARIA-E that participated in clinical trial with bapineuzumab, and we now propose to use the mouse version of bapineuzumab, monoclonal 3D6 exclusively for passive anti-Ab immunotherapy in 5xFAD Tg mice. Aim 1: To investigate the temporal sequence and the vascular aging components that contribute to the adverse CNS blood vessel responses to passive anti-Ab immunotherapy First, we will investigate the temporal sequence events including BBB dysfunction, myeloid cell activation and microhemorrhage formation in response to anti-Aβ immunotherapy in 5xFAD mice. Secondly, we will probe the role of age on vascular dysfunction and impairment of CSF dynamics in response to immunotherapy. Aim 2: Investigate the role of human APOE4 versus APOE3 in CNS blood vessel responses to passive anti-Ab immunotherapy causing ARIA-E and ARIA-H and other adverse cerebrovascular responses We propose to utilize 5xFAD crossed with APOE3 KI and APOE4 KI to investigate the increased risk for individuals with ApoE4 genotype to develop BBB dysfunction and cerebral microhemorrhages (ARIA-H) in response to anti-Aβ immunotherapy. Aim 3: Investigating the “cellular mechanisms” underlying the CNS blood vessel responses to passive anti-Ab immunotherapy that result in ARIA-E and ARIA-H and other adverse vascular events We will use two approaches to ablate specific effector cell populations in the CNS. In addition, we utilize a novel method to enhance perivascular macrophage (PVM) function to clear CAA and strengthen the BBB. Aim 4: Exploration of the “molecular mechanisms” underlying the brain blood vessel responses to passive anti-Ab immunotherapy that result in ARIA-E and ARIA-H and other adverse vascular events We plan to explore 3 molecular mechanisms to intervene in BBB responses to passive anti-Ab immunotherapy by utilizing: Lipoxin A4 an anti-inflammatory and pro-resolution agent ; a selective gelatinase MMP-2 and MMP-9 inhibitor SB-3CT that crosses the BBB; and a complement cascade inhibitor PMX205, a C5aR1 inhibitor that blocks the action of C5a, a highly proinflammatory anaphylatoxin.