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Soluble epoxide hydrolase is a key enzyme converting anti-inflammatory epoxy fatty acids to pro-inflammatory diols, reported to be elevated in multiple cardiometabolic disorders. Here we analyzed over 700 fasting plasma samples from the baseline of Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI) 2\/GO study. We applied targeted mass spectrometry method to provide absolute quantifications of over 150 metabolites from oxylipin and endocannabinoids pathway, interrogating the role for inflammation\/immune dysregulation and the key enzyme soluble epoxide hydrolase in AD. We provide further insights into the regulation of this pathway in different disease stages, APOE genotypes and between sexes. Additionally, we investigated in mild cognitive impaired (MCI) patients, metabolic signatures that inform about resilience to progression and conversion to AD. Key findings include I) confirmed disruption in this key central pathway of inflammation and pointed to dysregulation of sEH in AD with sex and disease stage differences; II) identified markers of disease progression and cognitive resilience using sex and ApoE genotype stratified analysis highlighting an important role for bile acids, lipid peroxidation and stress response hormone cortisol. In conclusion, we provide molecular insights into a central pathway of inflammation and links to cognitive dysfunction, suggesting novel therapeutic approaches that are based on targeting inflammation tailored for subgroups of individuals based on their sex, APOE genotype and their metabolic profile.<\/jats:p>","DOI":"10.1101\/2025.04.01.646677","type":"posted-content","created":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T20:00:13Z","timestamp":1743710413000},"source":"Crossref","is-referenced-by-count":5,"title":["Metabolic Alteration in Oxylipins and Endocannabinoids Point to an Important Role for Soluble Epoxide Hydrolase and Inflammation in Alzheimer\u2019s Disease - Finding from Alzheimer\u2019s Disease Neuroimaging Initiative"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3637-3450","authenticated-orcid":false,"given":"Kamil","family":"Borkowski","sequence":"first","affiliation":[{"name":"West Coast Metabolomics Center, Genome Center, University of California Davis, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyuan","family":"Yin","sequence":"additional","affiliation":[{"name":"Metabolomics and Analytics Centre, Leiden Academic Center for Drug Research, Leiden University, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alida","family":"Kindt","sequence":"additional","affiliation":[{"name":"Metabolomics and Analytics Centre, Leiden Academic Center for Drug Research, Leiden University, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuanyi","family":"Liang","sequence":"additional","affiliation":[{"name":"West Coast Metabolomics Center, Genome Center, University of California Davis, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"de Lange","sequence":"additional","affiliation":[{"name":"Research Division of Systems Pharmacology and Pharmacy, LACDR, Leiden University, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colette","family":"Blach","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Duke Institute for Brain Sciences and Department of Medicine, Duke University, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Newman","sequence":"additional","affiliation":[{"name":"West Coast Metabolomics Center, Genome Center, University of California Davis, Davis, CA 95616, USA"},{"name":"Western Human Nutrition Research Center, United States Department of Agriculture - 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