. 2025 Oct;21(10):e70718.

doi: 10.1002/alz.70718.

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

Si Won Ryoo^{1

2

3}, William Z Lin², Alexandra Magliocco¹, Myuri Ruthirakuhan², Yuen Yan Wong^{1

2}, Sofia E Perfetto^{1

2

3}, Celine Huang^{1

2

3}, Natasha Z Anita⁴, Stephen R Arnott⁵, Anthony E Lang^{6

7

8

9}, Sean Symons^{2

10

11

12}, Robert A Hegele^{13

14}, Maged Goubran^{2

12

15}, Joel Ramirez², Julie Ottoy^{2

6

12}, Jennifer S Rabin^{2

6

16

17}, Bradley J MacIntosh^{2

12

15}, Krista L Lanctôt^{1

2

3}, Nuanyi Liang¹⁸, Hugo Cogo-Moreira¹⁹, Ameer Y Taha¹⁸, Walter Swardfager^{1

2

3}; ONDRI Investigators

Affiliations

¹ Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
² Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
³ KITE Research Institute, Toronto Rehabilitation Institute - University Health Network, Toronto, Ontario, Canada.
⁴ Department of Neurosciences, University of California San Diego, San Diego, California, USA.
⁵ Indoc Systems, Toronto, Ontario, Canada.
⁶ Division of Neurology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁷ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada.
⁸ Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
⁹ Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
¹⁰ Department of Medical Imaging, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
¹¹ Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
¹² Physical Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
¹³ Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
¹⁴ Division of Endocrinology and Metabolism, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
¹⁵ Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
¹⁶ Harquail Centre for Neuromodulation, Sunnybrook Research Institute, Toronto, Ontario, Canada.
¹⁷ Rehabilitation Sciences Institute, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Department of Food Science and Technology, College of Agriculture and Environmental Sciences, University of California Davis, Davis, California, USA.
¹⁹ Department of Education, ICT and Learning, Østfold University College, Halden, Norway.

PMID: 41059602
PMCID: PMC12505018
DOI: 10.1002/alz.70718

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

Si Won Ryoo et al. Alzheimers Dement. 2025 Oct.

. 2025 Oct;21(10):e70718.

doi: 10.1002/alz.70718.

Authors

Affiliations

¹ Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
² Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
³ KITE Research Institute, Toronto Rehabilitation Institute - University Health Network, Toronto, Ontario, Canada.
⁴ Department of Neurosciences, University of California San Diego, San Diego, California, USA.
⁵ Indoc Systems, Toronto, Ontario, Canada.
⁶ Division of Neurology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁷ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada.
⁸ Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
⁹ Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
¹⁰ Department of Medical Imaging, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
¹¹ Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
¹² Physical Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
¹³ Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
¹⁴ Division of Endocrinology and Metabolism, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
¹⁵ Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
¹⁶ Harquail Centre for Neuromodulation, Sunnybrook Research Institute, Toronto, Ontario, Canada.
¹⁷ Rehabilitation Sciences Institute, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Department of Food Science and Technology, College of Agriculture and Environmental Sciences, University of California Davis, Davis, California, USA.
¹⁹ Department of Education, ICT and Learning, Østfold University College, Halden, Norway.

PMID: 41059602
PMCID: PMC12505018
DOI: 10.1002/alz.70718

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.

Keywords: biomarkers; cerebral small vessel disease; cerebrovascular disease; cognition; diabetes; neurodegenerative disease; neuroimaging; oxylipins.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Associations between PVS volumes and (A) 9,10‐DiHOME/9(10)‐EpOME ratio and (B) 12,13‐DiHOME/12(13)‐EpOME ratio in the whole group. DiHOME, dihydroxyoctadecamonoenoic acid; EpOME, epoxyoctadecamonoenoic acid; PVS, perivascular spaces.

**FIGURE 2**
Associations between SVD markers and (A) 9,10‐DiHOME/9(10)‐EpOME ratio and (B) 12,13‐DiHOME/12(13)‐EpOME ratio in individuals with normoglycemia, prediabetes, or T2DM. The standardized regression coefficients and 95% confidence intervals in individuals with normoglycemia are represented in blue, prediabetes are represented in green, and T2DM are represented in red. DiHOME, dihydroxyoctadecamonoenoic acid; EpOME, epoxyoctadecamonoenoic acid; PVS, perivascular space; SVD, cerebral small vessel disease; T2DM, type 2 diabetes mellitus; WMH, white matter hyperintensity.

**FIGURE 3**
Associations between global brain parenchymal fraction and (A) 9,10‐DiHOME/9(10)‐EpOME ratio and (B) 12,13‐DiHOME/12(13)‐EpOME ratio in individuals with normoglycemia (blue), prediabetes (green), and T2DM (red). BPF, brain parenchymal fraction; DiHOME, dihydroxyoctadecamonoenoic acid; EpOME, epoxyoctadecamonoenoic acid.

**FIGURE 4**
Associations between regional brain parenchymal fraction and (A) 9,10‐DiHOME/9(10)‐EpOME ratio and (B) 12,13‐DiHOME/12(13)‐EpOME ratio in individuals with normoglycemia (blue), prediabetes (green), or T2DM (red). The standardized regression coefficients and 95% confidence intervals in each group are represented by the dot and line, respectively. DiHOME, dihydroxyoctadecamonoenoic acid; EpOME, epoxyoctadecamonoenoic acid; T2DM, type 2 diabetes mellitus.

**FIGURE 5**
Associations between executive function and (A) 9,10‐DiHOME/9(10)‐EpOME ratio and (B) 12,13‐DiHOME/12(13)‐EpOME ratio and association between memory and (C) 9,10‐DiHOME/9(10)‐EpOME ratio and (D) 12,13‐DiHOME/12(13)‐EpOME ratio in individuals with normoglycemia (blue), prediabetes (green), and T2DM (red). DiHOME, dihydroxyoctadecamonoenoic acid; EpOME, epoxyoctadecamonoenoic acid; T2DM, type 2 diabetes mellitus.

See this image and copyright information in PMC

References

1. Cholerton B, Baker LD, Montine TJ, Craft S. Type 2 Diabetes, Cognition, and Dementia in Older Adults: toward a Precision Health Approach. Diabetes Spectr Publ Am Diabetes Assoc. 2016;29:210‐219. doi: 10.2337/ds16-0041 - DOI - PMC - PubMed
1. Gudala K, Bansal D, Schifano F, Bhansali A. Diabetes mellitus and risk of dementia: a meta‐analysis of prospective observational studies. J Diabetes Investig. 2013;4:640‐650. doi: 10.1111/jdi.12087 - DOI - PMC - PubMed
1. Wang D‐Q, Wang L, Wei M‐M, et al. Relationship Between Type 2 Diabetes and White Matter Hyperintensity: a Systematic Review. Front Endocrinol. 2020;11:595962. doi: 10.3389/fendo.2020.595962 - DOI - PMC - PubMed
1. Cannistraro RJ, Badi M, Eidelman BH, Dickson DW, Middlebrooks EH, Meschia JF. CNS small vessel disease. Neurology. 2019;92:1146‐1156. doi: 10.1212/WNL.0000000000007654 - DOI - PMC - PubMed
1. McReynolds C, Morisseau C, Wagner K, Hammock B. Epoxy Fatty Acids Are Promising Targets for Treatment of Pain, Cardiovascular Disease and Other Indications Characterized by Mitochondrial Dysfunction, Endoplasmic Stress and Inflammation. Adv Exp Med Biol. 2020;1274:71‐99. doi: 10.1007/978-3-030-50621-6_5 - DOI - PMC - PubMed

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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

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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

Authors

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Abstract

Conflict of interest statement

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