Metabolic and vascular contributions to dementia: Soluble epoxide hydrolase‐derived linoleic acid oxylipins and glycemic status are related to cerebral small vessel disease markers, atrophy, and cognitive performance

Abstract INTRODUCTION Type 2 diabetes mellitus (T2DM) is a risk factor for dementia and cerebral small vessel disease, but there remains a need to identify targetable molecular pathways involved in the underlying pathophysiology. METHODS In participants with Alzheimer's disease, related dementias, or cerebrovascular diseases, we assessed associations between ratios of unesterified linoleic acid (LA)‐derived soluble epoxide hydrolase (sEH) metabolites (diols) and substrates (epoxides), with imaging‐derived white matter hyperintensities (WMHs), brain parenchymal fraction (BPF), and cognitive performance. Potential moderation effects by glycemic control (hemoglobin A1c [HbA1c]) were examined. RESULTS With elevated HbA1c, greater LA‐derived diol/epoxide ratios were associated with greater WMH volume ( β [95% CI] = 0.565 [0.100, 1.030], p = 0.017), lower global BPF ( β [95% CI] = −0.476 [−0.903, −0.048], p = 0.029), and poorer memory performance ( β [95% CI] = −0.603 [−1.070, −0.136], p = 0.012), such that detrimental associations were observed only in T2DM. DISCUSSION Cytochrome P450‐sEH metabolites may indicate a novel metabolic‐vascular contribution to dementia in individuals with T2DM. CLINICAL TRIALS REGISTRATION INFORMATION ClinicalTrials.gov Identifier NCT04104373. Highlights LA‐derived sEH metabolite (diol) to substrate (epoxide) ratio was lower in individuals with diabetes. The diol/epoxide ratio with high HbA1c contributed to SVD and brain atrophy. The CYP450‐sEH pathway may link metabolic and vascular contributions to dementia. sEH may be a potential therapeutic target in individuals with diabetes.