Alzheimer's disease (AD) is a condition that mostly affects elderly individuals who are also at an increased risk of cerebrovascular disease. It is not well known if AD pathology results in poorer outcomes for cerebral ischemia. In the current study, we hypothesized that a brain affected by AD is vulnerable to cerebral ischemia, resulting in greater necrosis and neuronal cell death by inducing cerebral amyloid beta (Aβ) and tau protein accumulation, as well as degenerative changes. In this study, the effect of transient cerebral ischemia induced by bilateral carotid artery occlusion, which is often used as a vascular dementia model, was assessed in a transgenic (TG) mouse model of AD (3xTG-AD). After 15 minutes of bilateral carotid artery occlusion, followed by reperfusion, we evaluated cognitive changes, extent of neuronal death, and dementia-specific neuropathological changes compared with wild-type (WT) mice. Results of behavioral studies demonstrated that TG mice exposed to cerebral ischemia showed greater deficits in spatial learning and memory than similarly treated WT mice. Cognitive impairment in TG mice might be attributed to greater neuronal cell death due to brain ischemia compared with WT mice. However, similar Aβ accumulation was observed in both groups. Expression of caspase-3, Iba-1, and GFAP was increased in ischemic TG mice. In conclusion, our results suggest that Alzheimer’s neuropathology can trigger changes that make AD brains more vulnerable to cerebral ischemia/reperfusion.