Peripheral cytochrome P450-soluble epoxide hydrolase oxylipins and Alzheimer’s disease progression

Oxylipin species are generated from omega-3 and omega-6 fatty acids during inflammation, including fatty acid epoxides by cytochrome P450s (CYP450) and their diol metabolites by soluble epoxide hydrolase (sEH). The CYP450-sEH pathway has been implicated in Alzheimer’s disease (AD) but it remains unclear how plasma oxylipins relate to AD biomarkers and neurodegeneration. Fasting plasma CYP450-sEH total (free + esterified) oxylipins were assayed by ultra-high pressure liquid chromatography-tandem mass spectrometry in participants (NCT04104373) clinically diagnosed with AD or mild cognitive impairment (MCI). Plasma AD biomarkers were assayed by SiMoA. At baseline, 1 and 2 years, regional grey matter and white matter hyperintensity (WMH) volumes were quantified using 3.0 T MRI, and cognitive assessments were performed. At baseline ( n = 125), participants with AD vs. MCI had higher CYP450-sEH pathway metabolites, apolipoprotein E ( APOE) ε4 carriers vs. non-carriers had higher diol levels, and females vs. males had higher omega-6 vs. omega-3 oxylipins. An oxylipin profile of higher diols and lower epoxides was associated with higher pTau181, temporal lobe and hippocampal atrophy, and declines in cognitive performance in multiple domains over 2 years. Higher CYP450-sEH pathway metabolites were associated with the progression of WMH. Larger oxylipin relationships with atrophy and cognitive decline were seen at the MCI stage, in APOE ε4 carriers, and in females. Elevated sEH metabolites were related to biomarkers of AD pathogenesis, and they predicted atrophy, white matter changes, and cognitive decline over 2 years.