The epidemiological link between hypertension and Alzheimer disease is established. We previously reported that hypertension aggravates the Alzheimer-like pathology in APPPS1 mice (amyloid precursor protein/presenilin-1, mouse model of Alzheimer disease) with angiotensin II–induced hypertension, in relation with hypertension and nitric oxide deficiency. To provide further insights into the role of nitric oxide in the hypertension—Alzheimer disease cross-talk, we studied the effects of nitric oxide blockade in APPPS1 mice using N(ω)-nitro-L-arginine methyl ester (L-NAME) alone or in combination with hydralazine, to normalize blood pressure. Compared with normotensive APPPS1 mice, those with L-NAME–induced hypertension had greater amyloid burden (P<0.05), increased cortical amyloid angiopathy (P<0.01), decreased regional microvascular density (P<0.05), and deficient long-term spatial reference memory (P<0.001). Blood pressure normalization with hydralazine did not protect APPPS1 mice from L-NAME–induced deterioration except for cortical amyloid angiopathy, linked to hypertension-induced arterial wall remodeling. By testing the cerebrovascular response to hypercapnic breathing, we evidenced early functional impairment of cerebral vasomotor activity in APPPS1 mice. Whereas in control wild-type normotensive mice, carbon dioxide breathing resulted in 15±1.3% increase in the mean blood flow velocity (P<0.001), paradoxical mild decrease (1.5±0.4%) was recorded in normotensive APPPS1 mice (P<0.001). Carbon dioxide–induced decrease in mean blood flow velocity was not significantly modified in L-NAME–treated hypertensive APPPS1 mice (2.5±1.2%) and partly reversed to mild vasodilation by hydralazine (3.2±1.5%, P<0.01). These results suggest that impaired nitric oxide bioavailability exacerbates the pathophysiology of Alzheimer disease, essentially impacting amyloid load and cognitive impairment, independently of L-NAME–induced hypertension. Only cerebral amyloid angiopathy seems to be dependent on hypertension.