A chronic and gradual increase in pulse pressure (PP) is associated with cognitive decline and dementia in older individuals, but the mechanisms remain ill-defined. We hypothesized that a chronic elevation of PP would cause brain microvascular endothelial mechanical stress, damage the neurovascular unit, and ultimately induce cognitive impairment in mice, potentially contributing to the progression of vascular dementia and Alzheimer disease. To test our hypothesis, male control wild-type mice and Alzheimer disease model APP/PS1 (amyloid precursor protein/presenilin 1) mice were exposed to a transverse aortic constriction for 6 weeks, creating a PP overload in the right carotid (ipsilateral). We show that the transverse aortic constriction procedure associated with high PP induces a cascade of vascular damages in the ipsilateral parenchymal microcirculation: in wild-type mice, it impairs endothelial dilatory and blood brain barrier functions and causes microbleeds, a reduction in microvascular density, microvascular cell death by apoptosis, leading to severe hypoperfusion and parenchymal cell senescence. These damages were associated with brain inflammation and a significant reduction in learning and spatial memories. In APP/PS1 mice, that endogenously display severe cerebral vascular dysfunctions, microbleeds, parenchymal inflammation and cognitive dysfunction, transverse aortic constriction-induced high PP further aggravates cerebrovascular damage, Aβ (beta-amyloid) accumulation, and prevents learning. Our study, therefore, demonstrates that brain microvessels are vulnerable to a high PP and mechanical stress associated with transverse aortic constriction, promoting severe vascular dysfunction, disruption of the neurovascular unit, and cognitive decline. Hence, chronic elevated amplitude of the PP could contribute to the development and progression of vascular dementia including Alzheimer disease.