# Total plasma cytochrome P450‐soluble epoxide hydrolase oxylipins, apolipoprotein E ε4 carrier status, and white matter hyperintensities in cerebrovascular disease

## TL;DR

This study explores how certain blood chemicals and a genetic factor (APOE ε4) relate to brain changes in cerebrovascular disease.

## Contribution

The study reveals how APOE ε4 status modifies the relationship between CYP450-sEH pathway oxylipins and white matter hyperintensities.

## Key findings

- Omega-3-derived epoxides and diols were linked to greater pWMH volumes in APOE ε4 non-carriers.
- APOE ε4 carriers showed attenuated associations between oxylipins and pWMH volumes.
- Linoleic acid diol/epoxide ratios were associated with dWMH volumes only in APOE ε4 non-carriers.

## Abstract

The cytochrome P450‐soluble epoxide hydrolase (CYP450‐sEH) pathway has been implicated in cerebral small vessel disease (cSVD) due to the anti‐inflammatory and vasoactive effects of epoxide species produced by CYP450, which are converted into diols by sEH. However, the associations between total oxylipins and cSVD markers and the interactions with other risk factors (e.g., apolipoprotein E ε4 or APOE ε4 allele) remain unclear.

Participants diagnosed with cerebrovascular disease were identified from the Ontario Neurodegenerative Disease Research Initiative study. Periventricular and deep white matter hyperintensity (pWMH/dWMH) volumes at baseline were quantified using MRI images processed using a semi‐automated pipeline. 24 arachidonic, linoleic, eicosapentaenoic, and docosahexaenoic acid‐derived oxylipins were extracted from plasma with Folch extraction followed by hydrolysis, solid‐phase extraction, and quantification with LC‐MS/MS. Diol to epoxide ratios were calculated as a proxy for sEH activity. Cross‐sectional associations were examined using linear regression models between log‐transformed WMH volumes and log‐transformed oxylipin concentrations, including age, sex, diabetes, hypertension, creatinine, cholesterol, triglycerides, and presence of the APOE ε4 allele as covariates. Stratified analyses were performed within APOE ε4 carrier and non‐carrier subgroups.

Across 159 participants (67.9% male, mean age = 69.2 years), the eicosapentaenoic acid‐derived 11(12)‐epoxyeicosatetraenoic acid (EpETE) (β = 0.157, p = 0.034) and 14(15)‐EpETE (β = 0.155, p = 0.039) were positively associated with pWMH volumes. The 11,12‐dihydroxyeicosatetraenoic acid was also positively associated with pWMH volumes (β = 0.157, p = 0.031). The 9(10)‐linoleic acid diol/epoxide ratio was associated with greater dWMH volumes (β = 0.186, p = 0.031). In subgroup analyses, all omega‐3‐derived epoxides and diols were associated with greater pWMH volumes in APOE ε4 non‐carriers (β = 0.191 to 0.257, p = 0.027 to 0.002), whereas these effects were attenuated in APOE ε4 carriers. The 9(10)‐ and 12(13)‐linoleic acid diol/epoxide ratios were positively associated with dWMH volumes only in APOE ε4 non‐carriers.

In individuals with cerebrovascular disease, APOE ε4 carrier status may moderate associations between CYP‐sEH oxylipins and WMH volumes. Studies of interventions targeting this pathway should consider stratification based on APOE genotype.