Assessing the effect of eicosapentaenoic acid (EPA) on CSF levels of matrix metalloproteinases and their inhibitors

Sep 30, 2026

Uploaded by Oliver

Matrix metalloproteinases (MMPs) regulate extracellular matrix integrity and inflammation and can degrade beta-amyloid fibrils, yet evidence on how eicosapentaenoic acid (EPA) affects these enzymes in cerebrospinal fluid (CSF) remains limited. This study assessed an FDA-approved high-dose EPA supplement’s impact on CSF MMP-2, MMP-9, TIMP-1, and TIMP-2 using samples collected at baseline, 9 months, and 18 months.

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CategoryHealthcare

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DOI: 10. 1002/alz70856_106642 BIOMARKERS POSTER PRESENTATION BIOMARKERS (NON-NEUROIMAGING) Assessing the effect of eicosapentaenoic acid (EPA) on CSF levels of matrix metalloproteinases and their inhibitors Samantha L. Shapiro 1, 2 CarolA. Van Hulle3, 4 Aimee K Johnson 1 Hannah Zylstra3, 4 Kate Cronin3, 4 Aleshia Cole3, 4 Elena Beckman3 Allison C Eierman3 Richard J. Chappell2, 3 Sanjay Asthana3, 4 Carey E. Gleason3, 4, 5 Henrik Zetterberg2, 6, 7, 8, 9 Sterling C. Johnson3, 4, 10 Anthony P Auger 11, 12 Cynthia M. Carlsson3,4, 5, 10 1 University of Wisconsin-Madison, Madison, WI, USA 2 University of Wisconsin School of Medicine and Public Health, Madison, WI, USA 3Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA 4 Division of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA 5 Geriatric Research, Education and Clinical Center (GRECC), William S. Middleton Memorial Veterans Hospital, Madison, WI, USA 6 UK Dementia Research Institute, UCL Institute of Neurology, University College London, London, England, United Kingdom 7 Hong Kong Center for Neurodegenerative Diseases, Hong Kong, Hong Kong, China 8 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden 9Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA 10Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA 11 University of Wisconsin-Madison, Department of Psychiatry, Madison, WI, USA Abstract Background: Matrix metalloproteinases (MMPs) are a group of enzymes with roles in mediating extracellular matrix integrity and inflammation, and degrading beta amyloid fibrils. Studies have demonstrated that MMPs in atherosclerotic plaques can be downregulated by omega-3 fatty acid eicosapentaenoic acid (EPA), but there has been little research looking at the effect of EPA on MMP levels in CSF. In this study, we evaluated the effect of an FDA approved high dose EPA supplement on CSF levels of MMP-2 and MMP-9, and MMP inhibitors TIMP-1 and TIMP-2. Method: Cognitively healthy VA-eligible veterans (ages 50-76) were enrolled in the Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid Study (BRAVE, NCT02719327), a randomized, placebo-controlled, double-blind, parallel-group clinical trial with subject N = 128, randomized in a 1:1 ratio to receive either 4gicosapent ethyl (Vascepa® IPE) or a placebo (mineral oil) daily for 18 months. Participants with suspected memory impairment, liver or kidney disease, or those unable to comply with study procedures were excluded. CSF biomarkers MMP-2, MMP-9, TIMP-1, and TIMP-2 were obtained at baseline, 9 months, and 18 months. In these exploratory analyses, treatment group differences in CSF biomarkers (18 month/baseline ratio) were analyzed on an intent to treat basis using GraphPad Prism®. Result: Contrary to published studies showing decreased levels and expression of MMP-2 and-9 in individuals treated with EPA, our data revealed significant increases in levels of MMP-2(p = 0.04)and MMP-9(p = 0.003)intheIPE treated group compared to placebo. There was also a significant increase in TIMP-2 in the IPE group (p = 0.02), This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2025 The Alzheimer’s Association. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association. Alzheimer’s Dement. 2025;21(Suppl. 2):e106642. [https://doi.org/10.1002/alz70856_106642](https://doi.org/10.1002/alz70856_106642) wi[leyonlinelibrary.com/

FAQs

What was the study evaluating regarding EPA?

The study evaluated how a high-dose EPA supplement affects CSF levels of matrix metalloproteinases (MMP-2, MMP-9) and their inhibitors (TIMP-1, TIMP-2).

Who participated in the randomized trial and what intervention was used?

Cognitively healthy VA-eligible veterans aged 50–76 were enrolled and randomized to receive 4 g icosapent ethyl (Vascepa® IPE) or placebo for 18 months.

What were the main findings on CSF biomarker levels?

Compared with placebo, the IPE group showed significant increases in CSF MMP-2 and MMP-9, and a significant increase in TIMP-2, based on an 18-month/baseline ratio analysis.

Sep 30, 2026

Uploaded by Oliver