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APOE4 carriers exhibit cerebral metabolic deficits decades before clinical onset. We previously demonstrated that ketogenic diet (KD), a low-carbohydrate, high-fat diet promoting ketone metabolism, confers cognitive benefits in aged C57BL\/6 mice, and in the PS1\/APP mouse model of early-onset AD. Here, we evaluated the effects of KD in a humanized APOE4 AD mouse model. KD significantly improved composite cognitive performance and spatial working memory, with pronounced effects in females. Synaptic plasticity, measured via long-term potentiation (LTP), was likewise enhanced exclusively in females. Transcriptomic and protein analyses revealed KD-induced activation of CREB pathway, marked by increased phosphorylation of ERK and CREB in female brains. Moreover, KD selectively reduced pro-inflammatory cytokine levels in females. These findings demonstrate sex-specific neuroprotective effects of KD in APOE4 mice and suggest its potential therapeutic role in mitigating AD risk in APOE4-positive women.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s11357-025-01998-8","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T08:46:48Z","timestamp":1763974008000},"page":"1937-1954","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A ketogenic diet improves memory in females in the APOE4 mouse model of Alzheimer\u2019s disease"],"prefix":"10.1007","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5312-5542","authenticated-orcid":false,"given":"Jacopo","family":"Di Lucente","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0046-7693","authenticated-orcid":false,"given":"Jennifer M.","family":"Rutkowsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6827-5412","authenticated-orcid":false,"given":"Alfredo","family":"Errico Provenzano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6720-0726","authenticated-orcid":false,"given":"Giuseppe","family":"Persico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6347-0646","authenticated-orcid":false,"given":"Zeyu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9729-1032","authenticated-orcid":false,"given":"Lee-Way","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1927-5365","authenticated-orcid":false,"given":"Jon J.","family":"Ramsey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1107-1029","authenticated-orcid":false,"given":"Claire B.","family":"Montgomery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8661-7508","authenticated-orcid":false,"given":"Kyoungmi","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5842-6042","authenticated-orcid":false,"given":"Marco","family":"Giorgio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8666-3520","authenticated-orcid":false,"given":"Izumi","family":"Maezawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2563-4133","authenticated-orcid":false,"given":"Gino A.","family":"Cortopassi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,24]]},"reference":[{"key":"1998_CR1","doi-asserted-by":"crossref","unstructured":"Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N and van Duijn CM. 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