Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the leading cause of dementia in the elderly. A recent positron emission tomography imaging study demonstrated upregulated brain arachidonic acid (AA) metabolism in AD patients. Further, a mouse model of AD shows an increase in AA-releasing cytosolic phospholipase A(2) (cPLA(2)) in brain, and a reduction in cPLA(2) activity ameliorated cognitive deficits. These observations led us to hypothesize that there is an upregulation of AA cascade and neuroinflammatory markers in the brain of AD patients. To test this hypothesis, we measured protein and mRNA levels of AA cascade, neuroinflammatory and synaptic markers in postmortem frontal cortex from 10 AD patients and 10 age-matched controls. Consistent with our hypothesis, AD frontal cortex showed significant increases in protein and mRNA levels of cPLA(2)-IVA, secretory sPLA(2)-IIA, cyclooxygenase-1 and -2, membrane prostaglandin (PG) synthase-1 and lipoxygenase-12 and -15. Calcium-independent iPLA(2)-VIA and cytosolic PGE(2) synthase were decreased. In addition, interleukin-1β, tumor necrosis factor-α, glial fibrillary acidic protein and CD11b were increased. AD postmortem brain also showed signs of cellular injury, including decreased synaptophysin and drebrin, pre- and postsynaptic markers. These results indicate that increased AA cascade and inflammatory markers could contribute to AD pathology. Altered brain AA cascade enzymes could be considered therapeutic targets for future drug development.