{"doi":"10.1007/s11357-025-01998-8","title":"A ketogenic diet improves memory in females in the APOE4 mouse model of Alzheimer’s disease","abstract":"The ε4 allele of apolipoprotein E (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD), increasing AD risk about fourfold in ~ 34 million American and ~ 75 million European females. 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.","journal":"GeroScience","year":2025,"id":515338,"datarank":0.3045363136359345,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.012649791277637431,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.012649791277637431,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":6,"citers_with_citation_signal":3,"citers_with_endowment":3,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9534,"is_data_producer":true,"deposit_databanks":{"GENBANK":["GSE301153"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":525525,"name":"Jennifer M. Rutkowsky","orcid":"0000-0002-0046-7693","position":1,"is_corresponding":false},{"id":1379591,"name":"Alfredo Errico Provenzano","orcid":"0000-0001-6827-5412","position":2,"is_corresponding":false},{"id":885802,"name":"Giuseppe Persico","orcid":"0000-0001-6720-0726","position":3,"is_corresponding":false},{"id":745754,"name":"Zeyu Zhou","orcid":"0000-0002-6347-0646","position":4,"is_corresponding":false},{"id":585338,"name":"Lee‐Way Jin","orcid":"0000-0001-9729-1032","position":5,"is_corresponding":false},{"id":293325,"name":"Jon J. Ramsey","orcid":null,"position":6,"is_corresponding":false},{"id":498937,"name":"Claire Montgomery","orcid":"0000-0002-1107-1029","position":7,"is_corresponding":false},{"id":442445,"name":"Kyoungmi Kim","orcid":"0000-0002-8661-7508","position":8,"is_corresponding":false},{"id":825647,"name":"Marco Giorgio","orcid":"0000-0002-5842-6042","position":9,"is_corresponding":false},{"id":322717,"name":"Izumi Maezawa","orcid":"0000-0002-8666-3520","position":10,"is_corresponding":false},{"id":479563,"name":"Gino Cortopassi","orcid":"0000-0003-2563-4133","position":11,"is_corresponding":false},{"id":322715,"name":"Jacopo Di Lucente","orcid":"0000-0001-5312-5542","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T02:48:39.436300Z","pmid":"41283974","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}