Alzheimer disease features amyloid-β (Aβ) peptide deposition in brain and blood vessels and is associated with hypertension. Aβ peptide can cause vasoconstriction and endothelial dysfunction. We observed that Aβ peptides exert a chronotropic effect in neonatal cardiomyocytes, similar to α₁-adrenergic receptor autoantibodies that we described earlier. Recently, it was shown that α₁-adrenergic receptor could impair blood–brain flow. We hypothesized that Aβ peptides might elicit a signal transduction pathway in vascular cells, induced by α₁-adrenergic receptor activation. Aβ (25–35) and Aβ (10–35) induced a positive chronotropic effect in the cardiac contraction assay (28.75±1.15 and 29.40±0.98 bpm), which was attenuated by α₁-adrenergic receptor blockers (urapidil, 1.53±1.17 bpm; prazosin, 0.30±0.96 bpm). Both Aβ peptides induced an intracellular calcium release in vascular smooth muscle cells. Chronotropic activity and calcium response elicited by Aβ (25–35) were blocked with peptides corresponding to the first extracellular loop of the α₁-adrenergic receptor. We observed an induction of extracellular-regulated kinase 1/2 phosphorylation by Aβ (25–35) in Chinese hamster ovary cells overexpressing α₁-adrenergic receptor, vascular smooth muscle cells, and cardiomyocytes. We generated an activation-state–sensitive α₁-adrenergic receptor antibody and visualized activation of the α₁-adrenergic receptor by Aβ peptide. Aβ (25–35) induced vasoconstriction of mouse aortic rings and in coronary arteries in Langendorff-perfused rat hearts that resulted in decreased coronary flow. Both effects could be reversed by α₁-adrenergic receptor blockade. Our data are relevant to the association between Alzheimer disease and hypertension. They may explain impairment of vascular responses by Aβ and could have therapeutic implications.