Association of plasma and CSF cytochrome P450, soluble epoxide hydrolase, and ethanolamide metabolism with Alzheimer’s disease

Authors: BORKOWSKI, KAMIL - University Of California, Davis; PEDERSEN, THERESA - University Of California, Davis; SEYFRIED, NICHOLAS - Emory University, School Of Medicine; LAH, JAMES - Emory University, School Of Medicine; LEVEY, ALLAN - Emory University; HALES, CHADWICK - Emory University; DAMMER, ERIC - Emory University, School Of Medicine; BLACH, COLLETE - Duke University; LOUIE, GREGORY - Duke University; KADDURAH-DAOUK, RIMA - Duke University; Newman, John

Submitted to: Alzheimer's Research & Therapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/25/2021
Publication Date: 9/6/2021
Citation: Borkowski, K., Pedersen, T.L., Seyfried, N.T., Lah, J.J., Levey, A.I., Hales, C.M., Dammer, E.B., Blach, C., Louie, G., Kaddurah-Daouk, R., Newman, J.W. 2021. Association of plasma and CSF cytochrome P450, soluble epoxide hydrolase, and ethanolamide metabolism with Alzheimer’s disease. Alzheimer's Research & Therapy. 13. Article 149. https://doi.org/10.1186/s13195-021-00893-6.
DOI: https://doi.org/10.1186/s13195-021-00893-6

Interpretive Summary: Alzheimer’s disease shares inflammatory origin with cardiometabolic disorders. Many lipid mediators are potent regulators of inflammation, energy metabolism and cell proliferation with well-established involvement in cardiometabolic diseases. However, their roles in Alzheimer’s disease is poorly understood. In the current study we provide a comprehensive analysis of plasma and cerebrospinal fluid (CSF) lipid mediators in a case-control comparison of patients with Alzheimer’s disease, utilizing a targeted quantitative mass spectrometry approach. In both plasma and CSF, we observed Alzheimer’s disease patients had elevated levels of epoxide and dihydroxy containing fatty acids, metabolites derived from the cytochrome P450/soluble epoxide hydrolase enzymatic pathway, and lower levels of fatty acids ethanolamides, a class of endogenous cannabinoid compounds. Plasma dihydroxy fatty acids together with ethanolamides were found to be strong and independent predictors for Alzheimer’s disease. Consistent with these findings, each of these metabolite classes are potent regulators of inflammation, and soluble epoxide hydrolase has been found to be upregulated in the brains of Alzheimer’s disease patients. This study provides further evidence for the involvement of inflammation in Alzheimer’s disease and argues for further research into the role of the cytochrome P450/soluble epoxide hydrolase pathway and fatty acid ethanolamides in this disorder. Further, these findings suggest that a combined pharmacological intervention targeting both metabolic pathways may have therapeutic benefits for Alzheimer’s disease.

Technical Abstract: Background: Alzheimer’s disease, cardiovascular disease and other cardiometabolic disorders may share inflammatory origins. Lipid mediators, including oxylipins, endocannabinoids, bile acids and steroids regulate inflammation, energy metabolism and cell proliferation with well-established involvement in cardiometabolic diseases. However, their roles in Alzheimer’s disease and their potential as biomarkers are poorly understood. Here we describe the analysis of plasma and cerebrospinal fluid lipid mediators in a case-control comparison of individuals with Alzheimer’s disease and healthy controls to investigate these knowledge gaps. Methods: Lipid mediators were measured using targeted quantitative mass spectrometry. Data were analyzed using analysis of covariates, adjusting for sex, age, and ethnicity. Partial least square discriminant analysis identified plasma and cerebrospinal fluid lipid mediator discriminates of Alzheimer’s disease. Alzheimer’s disease predictive models were constructed using machine learning combined with stepwise logistic regression. Results: In both plasma and cerebrospinal fluid, individuals with Alzheimer’s disease had elevated cytochrome P450/soluble epoxide hydrolase pathway components and decreased fatty acid ethanolamides compared to healthy controls. Circulating metabolites of soluble epoxide hydrolase and ethanolamides provide Alzheimer’s disease predictors with areas under receiver operator characteristic curves ranging from 0.82 to 0.92 for cerebrospinal fluid and plasma metabolites, respectively. Conclusions: Previous studies report Alzheimer’s disease-associated soluble epoxide hydrolase upregulation in the brain and that endocannabinoid metabolism provides an adaptive response to neuroinflammation. This study supports the involvement of P450-dependent and endocannabinoid metabolism in Alzheimer’s disease, yielding potential biomarkers of the disorder. The results further suggest that combined pharmacological intervention targeting both metabolic pathways may have therapeutic benefits for Alzheimer’s disease.