{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T10:35:04Z","timestamp":1782124504134,"version":"3.54.5"},"reference-count":69,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R21N2110628-01"],"award-info":[{"award-number":["R21N2110628-01"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Cure Alzheimers Fund","award":["2017 PJG"],"award-info":[{"award-number":["2017 PJG"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Late-onset Alzheimer\u2019s disease (LOAD) likely results from combinations of risk factors that include both genetic predisposition and modifiable lifestyle factors. The E4 allele of apolipoprotein E (ApoE) is the most significant genetic risk factor for LOAD. A Western-pattern diet (WD) has been shown to strongly increase the risk of cardiovascular disease and diabetes, conditions which have been strongly linked to an increased risk for developing AD. Little is known about how the WD may contribute to, or enhance, the increased risk presented by possession of the ApoE4 allele. To model this interaction over the course of a lifetime, we exposed male and female homozygote ApoE4 knock-in mice and wild-type controls to nine months of a high-fat WD or standard chow diet. At eleven months of age, the mice were tested for glucose tolerance and then for general activity and spatial learning and memory. Postmortem analysis of liver function and neuroinflammation in the brain was also assessed. Our results suggest that behavior impairments resulted from the convergence of interacting metabolic alterations, made worse in a male ApoE4 mice group who also showed liver dysfunction, leading to a higher level of inflammatory cytokines in the brain. Interestingly, female ApoE4 mice on a WD revealed impairments in spatial learning and memory without the observed liver dysfunction or increase in inflammatory markers in the brain. These results suggest multiple direct and indirect pathways through which ApoE and diet-related factors interact. The striking sex difference in markers of chronic neuroinflammation in male ApoE4 mice fed the high-fat WD suggests a specific mechanism of interaction conferring significant enhanced LOAD risk for humans with the ApoE4 allele, which may differ between sexes. Additionally, our results suggest researchers exercise caution when designing and interpreting results of experiments employing a WD, being careful not to assume a WD impacts both sexes by the same mechanisms.<\/jats:p>","DOI":"10.3390\/ijms23073921","type":"journal-article","created":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T21:22:39Z","timestamp":1648848159000},"page":"3921","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Sex Differences in Metabolic Indices and Chronic Neuroinflammation in Response to Prolonged High-Fat Diet in ApoE4 Knock-In Mice"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2575-3183","authenticated-orcid":false,"given":"Jennifer M.","family":"Mattar","sequence":"first","affiliation":[{"name":"Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Majchrzak","sequence":"additional","affiliation":[{"name":"George & Anne Ryan Institute for Neuroscience, University of Rhode Island, 130 Flagg Rd, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7431-7882","authenticated-orcid":false,"given":"Jaclyn","family":"Iannucci","sequence":"additional","affiliation":[{"name":"Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI 02881, USA"},{"name":"Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, 8447 Riverside Pkwy, Bryan, TX 77807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Bartman","sequence":"additional","affiliation":[{"name":"Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John K.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI 02881, USA"},{"name":"George & Anne Ryan Institute for Neuroscience, University of Rhode Island, 130 Flagg Rd, Kingston, RI 02881, USA"},{"name":"Department of Psychology, University of Rhode Island, 130 Flagg Rd, Kingston, RI 02881, USA"},{"name":"Department of Biomedical & Pharmaceutical Sciences, University of Rhode Island, 130 Flagg Rd, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Grammas","sequence":"additional","affiliation":[{"name":"George & Anne Ryan Institute for Neuroscience, University of Rhode Island, 130 Flagg Rd, Kingston, RI 02881, USA"},{"name":"Department of Biomedical & Pharmaceutical Sciences, University of Rhode Island, 130 Flagg Rd, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1001\/jama.1997.03550160069041","article-title":"Effects of Age, Sex, and Ethnicity on the Association between Apolipoprotein E Genotype and Alzheimer Disease. 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