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In addition, the sex-dependent effects of APOE on LOAD risk and endophenotypes have yet to be explained. In this Review, we revisit the different aspects of APOE involvement in neurodegeneration and neurological diseases, with particular attention to sex differences in the contribution of APOE to LOAD susceptibility. We discuss the role of APOE in a broader range of age-related neurodegenerative diseases, and summarize the biological factors linking APOE to sex hormones, drawing on supportive findings from rodent models to identify major mechanistic themes underlying the exacerbation of LOAD-associated neurodegeneration and pathology in the female brain. Additionally, we list sex-by-genotype interactions identified across neurodegenerative diseases, proposing APOE variants as a shared etiology for sex differences in the manifestation of these diseases. Finally, we present recent advancements in \u2018omics\u2019 technologies, which provide a new platform for more in-depth investigations of how dysregulation of this gene affects the development and progression of neurodegenerative diseases. Collectively, the evidence summarized in this Review highlights the interplay between APOE and sex as a key factor in the etiology of LOAD and other age-related neurodegenerative diseases. We emphasize the importance of careful examination of sex as a contributing factor in studying the underpinning genetics of neurodegenerative diseases in general, but particularly for LOAD.<\/jats:p>","DOI":"10.1242\/dmm.045211","type":"journal-article","created":{"date-parts":[[2020,8,27]],"date-time":"2020-08-27T13:55:11Z","timestamp":1598536511000},"source":"Crossref","is-referenced-by-count":84,"title":["Sex-dependent effect of <i>APOE<\/i> on Alzheimer's disease and other age-related neurodegenerative disorders"],"prefix":"10.1242","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3750-147X","authenticated-orcid":false,"given":"Julia","family":"Gamache","sequence":"first","affiliation":[{"name":"Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA"},{"name":"Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young","family":"Yun","sequence":"additional","affiliation":[{"name":"Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA"},{"name":"Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2529-8785","authenticated-orcid":false,"given":"Ornit","family":"Chiba-Falek","sequence":"additional","affiliation":[{"name":"Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA"},{"name":"Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2020,8,27]]},"reference":[{"key":"2021042700254412800_DMM045211C1","doi-asserted-by":"publisher","first-page":"12799","DOI":"10.1074\/jbc.M601019200","article-title":"24(S)-hydroxycholesterol participates in a liver X receptor-controlled pathway in astrocytes that regulates apolipoprotein E-mediated cholesterol efflux","volume":"281","author":"Abildayeva","year":"2006","journal-title":"J. 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