Neuritic pathology is a major neuroanatomical correlate of dementia in Alzheimer disease (AD). Nitric oxide (NO) is linked to neuritic growth and synaptic plasticity. Expression of one of the enzymes responsible for NO synthesis, the constitutive endothelial NO synthase (ceNOS), was investigated in brains of AD and Down syndrome patients using RNase protection assays, in situ hybridization, and immunocytochemistry. In end-stage AD, ceNOS expression was reduced in cortical neurons, and the enzyme was aberrantly translocated to membranes of proliferated swollen or collapsed neuritic processes. In addition, ceNOS expression was strikingly increased in glial cells characterized mainly as protoplasmic (Type 2) astrocytes, which are responsible for maintaining the structural and functional integrity of cell processes in the CNS. In Down syndrome, similar abnormalities emerged by the third decade, preceding the cognitive decline and establishment of CERAD criteria for AD, indicating that aberrant ceNOS expression occurs early in the course of neurodegeneration. The results suggest that aberrant ceNOS translocation and gene regulation may have important roles in the pathogenesis of AD neuritic pathology.