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Here, we examined codependent structural variations between the MTL\u2019s most vulnerable structure, the hippocampus (HC), and the DN at subregion resolution in individuals with Alzheimer\u2019s disease and related dementia (ADRD). By leveraging the power of the approximately 40,000 participants of the UK Biobank cohort, we assessed impacts from the protective<jats:italic>APOE<\/jats:italic>\u025b2 and the deleterious<jats:italic>APOE<\/jats:italic>\u025b4 Alzheimer\u2019s disease alleles on these structural relationships. We demonstrate \u025b2 and \u025b4 genotype effects on the inter-individual expression of HC-DN co-variation structural patterns at the population level. Across these HC-DN signatures, recurrent deviations in the CA1, CA2\/3, molecular layer, fornix\u2019s fimbria, and their cortical partners related to ADRD risk. Analyses of the rich phenotypic profiles in the UK Biobank cohort further revealed male-specific HC-DN associations with air pollution and female-specific associations with cardiovascular traits. We also showed that<jats:italic>APOE<\/jats:italic>\u025b2\/2 interacts preferentially with HC-DN co-variation patterns in estimating social lifestyle in males and physical activity in females. Our structural, genetic, and phenotypic analyses in this large epidemiological cohort reinvigorate the often-neglected interplay between<jats:italic>APOE<\/jats:italic>\u025b2 dosage and sex and link<jats:italic>APOE<\/jats:italic>alleles to inter-individual brain structural differences indicative of ADRD familial risk.<\/jats:p>","DOI":"10.1371\/journal.pbio.3001863","type":"journal-article","created":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T18:46:15Z","timestamp":1670957175000},"page":"e3001863","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["APOE alleles are associated with sex-specific structural differences in brain regions affected in Alzheimer\u2019s disease and related dementia"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7730-8324","authenticated-orcid":true,"given":"Chlo\u00e9","family":"Savignac","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Villeneuve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"AmanPreet","family":"Badhwar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Saltoun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimia","family":"Shafighi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Zajner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaibhav","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah A.","family":"Gagliano Taliun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sali","family":"Farhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judes","family":"Poirier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3466-6620","authenticated-orcid":true,"given":"Danilo","family":"Bzdok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,12,13]]},"reference":[{"key":"pbio.3001863.ref001","volume":"2018","author":"C. 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