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The APOE \u03b54 allele is the strongest genetic risk factor for late onset Alzheimer\u2019s disease and is a risk factor for VCID. Our lab has previously utilized a dietary model of hyperhomocysteinemia (HHcy) to induce VCID pathology and cognitive deficits in mice. This diet induces perivascular inflammation through cumulative oxidative damage leading to glial mediated inflammation and blood brain barrier breakdown. Here, we examine the impact of ApoE \u03b54 compared to \u03b53 alleles on the progression of VCID pathology and inflammation in our dietary model of HHcy. We report a significant resistance to HHcy induction in \u03b54 mice, accompanied by a number of related differences related to homocysteine (Hcy) metabolism and methylation cycle, or 1-C, metabolites. There were also significant differences in inflammatory profiles between \u03b53 and \u03b54 mice, as well as significant reduction in Serpina3n, a serine protease inhibitor associated with ApoE \u03b54, expression in \u03b54 HHcy mice relative to \u03b54 controls. Finally, we find evidence of pervasive sex differences within both genotypes in response to HHcy induction.<\/jats:p>","DOI":"10.1177\/0271678x211069006","type":"journal-article","created":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T06:50:21Z","timestamp":1642056621000},"page":"771-787","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":29,"title":["Apolipoprotein E \u03b54\/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling"],"prefix":"10.1177","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4124-7865","authenticated-orcid":false,"given":"Charles E","family":"Seaks","sequence":"first","affiliation":[{"name":"Sanders-Brown Center on Aging, Lexington, KY, USA"},{"name":"Department of Physiology, University of Kentucky, Lexington, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica 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