ApoE is a lipid transport protein enriched in brain and present in three allelic variants (e2, e3, e4). Homozygosity for the e4 allele (e4/e4) is the main genetic risk factor for Alzheimer’s disease, but ApoE4 carriers also have increased risk for white matter lesions in both vascular cognitive impairment and Alzheimer’s disease and related dementias. Subcortical and periventricular white matter damage is a major cause of age-related cognitive impairment, but the mechanisms remain elusive. Located at the borderzone between separate arterial territories, the deep white matter is highly vulnerable to hypoxia-ischemia. ApoE4 carriers have reduced cerebral blood flow, whereas mice expressing human ApoE4 exhibit a profound disruption of key mechanisms regulating the delivery of blood flow to the brain. These findings raise the possibility that such cerebrovascular dysregulation renders the deep white matter more susceptible to hypoxia-ischemia. Perivascular macrophages (PVM), brain resident myeloid cells closely apposed to the outer wall of cerebral pial and penetrating vessels, can produce ApoE, are enriched in ApoE receptors, and are a powerful source of vascular oxidative stress and inflammation. Therefore, we hypothesize that PVM-derived ApoE4 acts in an autocrine manner on PVM to produce vascular oxidative stress and inflammation, leading to neurovascular dysfunction and increased susceptibility to white matter injury. Since NOX2 is the main source of reactive oxygen species in macrophages and TRPM2 channels are critical for macrophage activation and neurovascular dysfunction, we will also examine their role. We will test the following hypotheses: (a) PVM are both a source and target of the ApoE4 mediating neurovascular dysfunction; (b) PVM TRPM2 channels and NOX2 mediate ApoE4-induced vascular oxidative stress and inflammation leading to neurovascular dysfunction; (c) PVM-derived ApoE4 is responsible for the increased susceptibility to oligemic WM damage through NOX2 and TRPM2 channels. Studies are conducted in young and old mice of both sexes with targeted replacement of mouse ApoE with human ApoE3 or 4. Deep white matter injury is produced in the corpus callosum by bilateral carotid artery stenosis using microcoils. Cutting-edge approaches are used, including 3-photon excited fluorescence to image the deep white matter and a novel mouse model enabling conditional gene targeting in PVM. These approaches allow us to assess microvascular perfusion and damage in the deep white matter in mice with ApoE4, NOX2, or TRPM2 deletion in PVM. These studies will provide insight into the mechanisms underlying the impact of ApoE4 on white matter damage and may unveil new therapeutic targets for one of the leading causes of cognitive impairment and dementia.