Metabolic alteration in oxylipins and endocannabinoids point to an important role for soluble epoxide hydrolase and inflammation in Alzheimer’s disease—finding from Alzheimer’s Disease Neuroimaging Initiative

Authors: BORKOWSKI, KAMIL - University Of California, Davis; YIN, CHUNYUAN - Leiden University; KINDT, ALIDA - Leiden University; LIANG, NUANYI - University Of California, Davis; DE LANGE, ELIZABETH - Leiden University; BLACH, COLETTE - Duke University; Newman, John; KADDURAH-DAOUK, RIMA - Duke University; HANKEMEIER, THOMAS - Leiden University

Submitted to: Alzheimer's Research & Therapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/9/2025
Publication Date: 1/7/2026
Citation: Borkowski, K., Yin, C., Kindt, A., Liang, N., de Lange, E., Blach, C., Newman, J.W., Kaddurah-Daouk, R., Hankemeier, T. 2026. Metabolic alteration in oxylipins and endocannabinoids point to an important role for soluble epoxide hydrolase and inflammation in Alzheimer’s disease—finding from Alzheimer’s Disease Neuroimaging Initiative. Alzheimer's Research & Therapy. 18(21). https://doi.org/10.1186/s13195-025-01939-9.
DOI: https://doi.org/10.1186/s13195-025-01939-9

Interpretive Summary: Mounting evidence implicates inflammation as a key factor in Alzheimer’s disease (AD) development. Soluble epoxide hydrolase converts anti-inflammatory epoxy fatty acids to pro-inflammatory diols, which is reported to be elevated in multiple cardiometabolic disorders. We previously found these pro-inflammatory diols to be elevated in the plasma and cerebrospinal fluid of AD patients and to be associated with lower cognition in non-AD subjects. Here we analyzed over 700 fasting plasma samples for 150 metabolites from oxylipin and endocannabinoids pathway and evaluated their changes at various AD diseases stages across sexes and apolipoprotein E genotypes, a known AD risk factor. The study provides molecular insights into a central pathway of inflammation with links to cognitive dysfunction, suggesting novel therapeutic approaches targeting inflammation tailored for subgroups of individuals based on their sex, APOE genotype and metabolic profile.

Technical Abstract: Mounting evidence implicates inflammation as a key factor in Alzheimer’s disease (AD) development. We previously identified pro-inflammatory soluble epoxide hydrolase (sEH) metabolites to be elevated in plasma and CSF of AD patients and to be associated with lower cognition in non-AD subjects. 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’s 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.