Several factors have been involved in Alzheimer’s disease (AD) but there is no definite conclusion as to the main pathogenic agents. Mutations in the amyloid precursor protein (APP) that lead to increased production of amyloid beta (Aβ) peptide are associated with the early onset, familial forms of AD. However, in addition to aging, the most common risk factors for the sporadic, prevalent form of AD are hypertension, hypercholesterolemia, ischemic stroke, the ApoE4 allele and diabetes, all characterized by a vascular pathology. In AD, the vascular pathology is essential to the diagnostic to the same extent as senile plaques, neurofibrillary tangles and neurodegenerative changes. Recently, chronic cerebral hypoperfusion has been proposed as an important factor in the cognitive deficits of AD. The vascular pathology in AD is characterized by the accumulation of Aβ in the vessel wall, atherosclerosis, vascular fibrosis, and structural changes of the blood vessels. Here, we used two transgenic mouse models that reproduce different but complementary aspects of the cerebrovascular pathology of AD to investigate the consequences on brain vascular functions. Mice overexpressed a mutated form of APP (APP mice) or an active form of the cytokine transforming growth factor-β1 (TGF-β1, TGF mice), and both have been shown previously to display cerebral hypoperfusion and hypometabolism. Using aged APP (>12 month-old) and TGF (>18 months) mice, we characterized their cerebrovascular responsiveness to vasoactive agonists, investigated alterations in proteins involved in vascular oxidative stress or vascular fibrosis, and compared changes in cortical microvessels and markers of oxidative stress to those found in brain and brain vessels from neuropathologically confirmed cases of AD. Additionally, we tested the effects of antioxidant therapy in vivo on the cerebrovascular dysfunctions induced by Aβ and TGF-β1. Aged mice were or not treated, and cerebrovascular functions (online videomicroscopy), vascular and neuronal protein alterations and, for APP mice, Aβ plaque load and soluble Aβ levels (Western blot and immunocytochemistry) were determined. The age was selected so that at the end of treatment, cerebrovascular dysfunctions in untreated mice would be fully manifest in order to best mimic the conditions seen in AD patients at the time of diagnostic. Aged APP mice displayed impaired dilatations to acetylcholine (ACh) and calcitonin gene-related peptide (CGRP), and a decreased contractile response to inhibition of nitric oxide synthase (NOS) as compared to wild-type controls. These alterations were associated with increased cerebrovascular levels of superoxide dismutase 2 (SOD2 or MnSOD), an antioxidant enzyme that is upregulated by its substrate superoxide, further supporting that Aβ exerts its deleterious effects on vascular functions through oxidative stress. Treatment with antioxidants Tempol or NAC (N-acetylcysteine) fully restored cerebrovascular functions in APP mice and normalized cerebrovascular SOD2 levels. Aβ plaque load and soluble levels of Aβ1-42 were unaltered by antioxidant therapy. Aged TGF mice exhibited impaired dilatations to ACh and CGRP, and decreased contractile responses to NOS inhibition or to endothelin-1 (ET-1) as compared to wild-type controls. These dysfunctions were accompanied by increased levels of collagen-IV, connective tissue growth factor (CTGF) and endothelin receptors type B (ETB receptors), which have all been associated with vascular fibrosis. The vascular alterations in these mice compared exquisitely well to that found in brain vessels of neuropathologically confirmed cases of AD. Antioxidant therapy was devoid of any beneficial effects on either cerebrovascular functions or protein alterations in TGF mice. These experiments show that oxidative stress is the major mechanism via which Aβ alters cerebrovascular functions, and this even at a very advanced stage of the pathology. Further, the results demonstrate that it is possible to fully reverse the Aβ-induced cerebrovascular dysfunctions in aged APP mice. However, as shown in the TGF mice, antioxidant therapy did not improve the TGF-β1-induced functional and structural alterations. These results indicate that antioxidants will have limited benefits in the cerebrovascular pathology of AD, in which both Aβ and TGF-β1 have been shown to be increased.