The cerebral microcirculation undergoes specific biochemical changes in Alzheimer′s disease. In this study, we have compared the nitric oxide synthase (NOS) activity of brain microvessels isolated from Alzheimer and control brains. L-[3H]-citrulline, the stable co-product generated with nitric oxide (NO) from L-[3H]-arginine, was measured as an indicator of NOS activity. The results indicated a significant increase in NOS activity in microvessels isolated from Alzheimer brains. In addition, using antibodies to both the endothelial and inducible NOS isoforms, we demonstrated a significant increase in enzyme level in Alzheimer-derived vessels. Elevated vascular production of NO, a potentially neurotoxic mediator in the CNS, may contribute to the susceptibility of neurons to injury and cell death in Alzheimer′s disease. © 1994 Academic Press, Inc.