Abstract: The sequence of events leading to neurodegeneration in Alzheimer's disease (AD) remains poorly understood. One prominent hypothesis is that neurovascular dysfunction contributes to both disease initiation and progression. Histologic analysis has supported this idea by demonstrating that vascular abnormalities are present early in the disease and most often perivascular amyloid deposits in the microvasculature. Two-photon in vivo imaging of mouse models of AD represents a unique approach to studying microvascular dysfunction in intact animals. We report here that a subpopulation of mice in early stages of AD (2–4 months) displays instability of vascular tone. Some, but not all animals exhibited oscillatory changes in arteriole diameter and poor vasodilation in response to sensory stimulation. An increased frequency of spontaneous astrocytic Ca2+ increases was noted in animals with unstable vasculature. Because astrocytes recently have been shown to control local microcirculation and contribute to functional hyperemia, we suggest that abnormal astrocytic activity may contribute to vascular instability in AD and thereby to neuronal demise.