Oxylipin composition of high-density lipoprotein is altered in men and Hispanic adults with mild cognitive impairment.

High-density lipoprotein (HDL) oxylipins are potent inflammatory mediators. HDL dyshomeostasis and inflammation increase mild cognitive impairment (MCI) and dementia risk, which vary by gender and race/ethnicity. It is unknown whether and how HDL oxylipin profiles differ between non-MCI and MCI individuals, or if potential differences are gender- and/or race/ethnicity dependent. In this targeted lipidomics study, we profiled plasma HDL oxylipins in older (70+) adults (N = 222) with or without MCI to determine how HDL oxylipin composition relates to cognitive impairment status. HDL oxylipin concentrations were analyzed by cognitive status, gender, and race/ethnicity (non-Hispanic Black, Hispanic, and non-Hispanic white). We found a gender- and race/ethnicity-specific association between MCI and lower HDL oxylipin content, which was independent of overall HDL-c concentrations. The HDL of MCI men contained lower amounts of anti-inflammatory and vasodilatory omega (ω)3 EPA C20:5ω3-derived hydroxyeicosapentaenoic acids (HEPEs) and DHA C22:6ω3-derived hydroxydocosahexaenoic acids than that of non-MCI men. Similarly, Hispanic participants with MCI had lower HDL concentrations of EPA C20:5ω3-derived HEPEs and DHA C22:6ω3-derived hydroxydocosahexaenoic acids than non-MCI Hispanic participants. Higher HDL concentrations of EPA C20:5ω3-derived HEPEs appeared protective against MCI in both men and Hispanic individuals. Further, higher oxylipin concentrations within HDL correlated with better cognition in non-Hispanic white women. This work identifying altered HDL oxylipin composition in MCI highlights a novel dysregulated lipid signaling pathway in cognitive decline. Reduced anti-inflammatory and vasodilatory ω3 oxylipins within HDL in MCI men and Hispanic individuals provide molecular evidence linking together HDL functionality, inflammation, and dementia risk.