Current evidence does not preclude the possibility that breach of the blood-brain barrier (BBB) is causally involved in the pathogenesis of Alzheimer disease (AD). There is abundant evidence, however, indicating morphological and biochemical abnormalities in the cerebral microvasculature that implicate breakdown of the BBB in AD. These abnormalities include profound irregularities in the course of vessels and the vascular basement membrane, changes in specific proteins and receptors associated with the cerebral endothelium, and increases in perivascular infiltrates. While noninvasive imaging and permeability studies provide no clear functional evidence to support the prevailing morphological evidence, focal and transient loss of integrity of the BBB in AD is probable. Thus, neuronal populations in circumscribed areas could become vulnerable. Cerebral amyloid angiopathy (CAA) is one of the pathological features highly associated with AD that may exacerbate the degenerative process. CAA may develop as a consequence of vascular changes at predisposed sites and precede at least some of the parenchymal amyloid deposits. It is not unlikely that many of these vascular changes contribute to the development of chronic hypoperfusion (or cerebrovascular insufficiency) that may lead to the progressive decline of cerebral functions in concert with aging.