Altered Epoxyeicosatrienoic Acid Signaling in Advanced-Stage Alzheimer's Disease (Investigation of Epoxyeicosatrienoic Acid Levels in Patients with Advanced Alzheimer's Disease).

INTRODUCTION: The study aimed to compare plasma Epoxyeicosatrienoic Acid (EET) isomers (5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET) in patients with advanced-stage late-onset Alzheimer's Disease (AS-LOAD) versus healthy controls matched by age and sex. METHODS: In this cross-sectional case-control study, 30 patients with AS-LOAD were compared with 30 cognitively healthy (control) individuals. Plasma EET levels were analyzed by liquid chromatography coupled with Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS). RESULTS: Plasma concentrations of all measured EET regioisomers were significantly lower in patients with AS-LOAD compared with controls. Significant reductions were observed for 14,15-EET (p = 0.007), 11,12-EET (p = 0.001), 8,9-EET (p = 0.007), and 5,6-EET (p = 0.011). DISCUSSION: EETs are reportedly implicated in AD development, with most previous investigations using animal models and targeted enzymes involved in EET metabolism, particularly soluble epoxide hydrolase (sEH). Furthermore, no studies have specifically examined EET metabolism in patients with advanced AD. This study revealed defective EET signaling with consequent increased sEH activity in AS-LOAD, suggesting that decreased EET might contribute to tau-mediated neurodegeneration, oxidative stress, and neuroinflammation in these patients. CONCLUSION: This study emphasizes the crucial role of EETs in AD pathology. Targeting EET metabolism could offer a promising therapeutic strategy for preventing AD. Studies that track disease progression are therefore a prerequisite for delaying its disease onset; thus, larger-scale longitudinal studies are needed to confirm these findings.