Epidemiological studies indicate that long-term treatment with non-steroidal anti-inflammatory drugs reduces the risk of Alzheimer Disease and may delay its onset or slow its progression. Neuroinflammation occurs in vulnerable regions of the Alzheimer's disease (AD) brain where highly insoluble beta-amyloid (Abeta) peptide deposits and neurofibrillary tangles, as well as damaged neurons and neurites, provide stimuli for inflammation. To elucidate the complex role of inflammation in neurodegenerative processes and the efficacy of selective COX-2 inhibitors in AD, we examined whether the attenuation of brain inflammatory reaction by selective COX-2 inhibitors may protect neurons against neurodegeneration. The data reported in this review show that in in vivo models of brain inflammation and neurodegeneration, the administration of selective COX-2 inhibitors prevent not only the inflammatory reaction, but also the cholinergic hypofunction. Our data may help elucidate the epidemiological findings indicating that anti-inflammatory agents, in particular NSAIDs, reduce the risk of developing AD and may slow its progression.