Ryoo_2025_Alzheimers.Dement_21_e70718

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 (beta [95% CI] = 0.565 [0.100, 1.030], p = 0.017), lower global BPF (beta [95% CI] = -0.476 [-0.903, -0.048], p = 0.029), and poorer memory performance (beta [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.