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Background: Chronic neuroinflammation is one of the hallmarks of late-onset Alzheimer’s disease (AD) dementia pathogenesis. Carrying the Apolipoprotein ε4 (APOE4) allele has been associated with an accentuated response to brain inflammation and increases the risk of AD dementia progression. Among inflammation signaling pathways, aberrant eicosanoid activation plays a prominent role in neurodegeneration. Methods: Using brains from the Religious Order Study (ROS), this study compared measures of brain eicosanoid lipidome in older persons with AD dementia to age-matched controls with no cognitive impairment (NCI), stratified by APOE genotype. Results: Lipidomic analysis of the dorsolateral prefrontal cortex demonstrated lower levels of omega-3 fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and DHA-derived neuroprotectin D1 (NPD-1) in persons with AD dementia, all of which associated with lower measures of cognitive function. In persons with dementia. A significant interaction was observed between carrying the APOE4 allele and higher levels of both pro-inflammatory lipids and pro-resolving eicosanoid lipids on measures of cognitive performance and on neuritic plaque burden. Furthermore, analysis of lipid metabolism pathways implicated activation of calcium dependent phospholipase A2 (cPLA2), 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH) enzymes. Conclusion: These findings implicate activation of the eicosanoid lipidome in the chronic unresolved state of inflammation in AD dementia, that is increased in carriers of the APOE4 allele, and identify potential therapeutic targets for resolving this chronic inflammatory state.