Cerebral amyloid angiopathy (CAA) caused by deposition of amyloid β (Aβ) peptides in the cerebrovasculature, involves degeneration of normal vascular components and increases the risk of infarction and cerebral hemorrhage. Accumulating evidence suggests that sporadic CAA is also a significant contributor to cognitive decline and dementia in the elderly. However, the mechanisms by which CAA arises are poorly understood. While neuronal sources of Aβ peptides are sufficient to cause CAA in transgenic mice overexpressing the amyloid precursor protein, there is reason to believe that in aging man, vascular disease modulates the disease process. To better understand CAA mechanisms in dementia, we assessed the frontal cortex of 62 consecutive cases of Alzheimer's disease (AD), vascular dementia (VaD), and mixed dementia (MD) using immunohistochemistry with antibodies to Aβ, smooth muscle actin and the carboxyl-terminal peptides to detect Aβ(40) and Aβ(42). While vascular Aβ deposition was invariably associated with smooth muscle degeneration as indicated by absence of smooth muscle cell actin reactivity, VaD/MD cases exhibited markedly more vascular Aβ(42) deposits and smooth muscle actin loss compared to AD cases with similar degrees of CAA and Aβ(40) deposition. This suggests that distinct mechanisms are responsible for the differential deposition of Aβ in CAA associated with AD and that associated with ischemic/cerebrovascular disease. It is plausible that experimental studies on the effects of cerebrovascular disease on Aβ production and elimination will yield important clues on the pathogenesis of CAA.