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However, the mechanisms by which ApoE4 contributes to AD pathogenesis are poorly understood. Here, we utilize a mouse model expressing either human ApoE3 or human ApoE4 to examine the effects of the E4 allele on a wide range of genetic and molecular pathways that are altered in early AD pathology. We demonstrate that ApoE4\u2010expressing mice begin to show early differential expression of multiple genes, leading to alterations in downstream pathways related to neural cell maintenance, insulin signaling, amyloid processing and clearance, and synaptic plasticity. These alterations may result in the earlier accumulation of pathological proteins such as \u03b2\u2010amyloid that may build up within cells, leading to the accelerated degeneration of neurons and astrocytes as observed in ApoE4\u2010positive individuals. We also examine the metabolic effects associated with a high\u2010fat diet (HFD) in male ApoE4\u2010expressing mice compared with regular chow diet (RD) fed mice at different ages. We found that young ApoE4\u2010expressing mice fed HFD developed metabolic disturbances, such as elevated weight gain, blood glucose, and plasma insulin levels that cumulatively have been observed to increase the risk of AD in humans. Taken together, our results reveal early pathways that could mediate ApoE4\u2010related AD risk and may help identify more tractable therapeutic targets for treating ApoE4\u2010associated AD.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15904-fig-0007-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.15904","type":"journal-article","created":{"date-parts":[[2023,7,7]],"date-time":"2023-07-07T00:06:11Z","timestamp":1688688371000},"page":"572-587","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Detection of early Alzheimer's disease\u2010like molecular alterations in a mouse model expressing human\n                    <scp>ApoE4<\/scp>"],"prefix":"10.1111","volume":"166","author":[{"given":"A.","family":"Rai","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine &amp; Dentistry University of Western Ontario  London Ontario Canada"},{"name":"Robarts Research Institute, Schulich School of Medicine &amp; Dentistry University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O. 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