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Although the reason for this association is not completely understood, researchers have uncovered numerous effects of <jats:italic>APOE4<\/jats:italic> expression on AD-relevant brain processes, including amyloid beta (A\u03b2) accumulation, lipid metabolism, endosomal-lysosomal trafficking, and bioenergetics. In this study, we aimed to determine the effect of <jats:italic>APOE4<\/jats:italic> allelic dosage on regional brain lipid composition in aged mice, as well as in cultured neurons. We performed a targeted lipidomic analysis on an AD-vulnerable brain region (entorhinal cortex; EC) and an AD-resistant brain region (primary visual cortex; PVC) from 14\u201315 month-old <jats:italic>APOE3\/3<\/jats:italic>, <jats:italic>APOE3\/4<\/jats:italic>, and <jats:italic>APOE4\/4<\/jats:italic> targeted replacement mice, as well as on neurons cultured with conditioned media from <jats:italic>APOE3\/3<\/jats:italic> or <jats:italic>APOE4\/4<\/jats:italic> astrocytes. Our results reveal that the EC possesses increased susceptibility to <jats:italic>APOE4<\/jats:italic>-associated lipid alterations compared to the PVC. In the EC, <jats:italic>APOE4<\/jats:italic> expression showed a dominant effect in decreasing diacylglycerol (DAG) levels, and a semi-dominant, additive effect in the upregulation of multiple ceramide, glycosylated sphingolipid, and bis(monoacylglycerol)phosphate (BMP) species, lipids known to accumulate as a result of endosomal-lysosomal dysfunction. Neurons treated with conditioned media from <jats:italic>APOE4\/4<\/jats:italic> vs. <jats:italic>APOE3\/3<\/jats:italic> astrocytes showed similar alterations of DAG and BMP species to those observed in the mouse EC. Our results suggest that <jats:italic>APOE4<\/jats:italic> expression differentially modulates regional neuronal lipid signatures, which may underlie the increased susceptibility of EC-localized neurons to AD pathology.<\/jats:p>","DOI":"10.1038\/s41398-022-01881-6","type":"journal-article","created":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T08:07:43Z","timestamp":1648541263000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0175-9938","authenticated-orcid":false,"given":"Andr\u00e9 Miguel","family":"Miranda","sequence":"first","affiliation":[]},{"given":"Archana","family":"Ashok","sequence":"additional","affiliation":[]},{"given":"Robin Barry","family":"Chan","sequence":"additional","affiliation":[]},{"given":"Bowen","family":"Zhou","sequence":"additional","affiliation":[]},{"given":"Yimeng","family":"Xu","sequence":"additional","affiliation":[]},{"given":"Laura Beth","family":"McIntire","sequence":"additional","affiliation":[]},{"given":"Estela","family":"Area-Gomez","sequence":"additional","affiliation":[]},{"given":"Gilbert","family":"Di Paolo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6177-868X","authenticated-orcid":false,"given":"Karen E.","family":"Duff","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0509-0562","authenticated-orcid":false,"given":"Tiago Gil","family":"Oliveira","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5252-8048","authenticated-orcid":false,"given":"Tal","family":"Nuriel","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2022,3,29]]},"reference":[{"key":"1881_CR1","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1038\/ng1197-263","volume":"17","author":"KR Bales","year":"1997","unstructured":"Bales KR, Verina T, Dodel RC, Du Y, Altstiel L, Bender M, et al. 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