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ApoE4 has reduced lipidation capacity and impaired lipid transport, disrupting neuronal maintenance. The high\u2010density lipoprotein (HDL)\u2010mimetic peptide 4F offers a potential therapeutic strategy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      To investigate how\n                      <jats:italic>APOE4<\/jats:italic>\n                      alters brain gene expression and lipid metabolism and to evaluate the therapeutic potential of 4F, we performed dual\u2010omics analysis in\n                      <jats:italic>APOE4\/4<\/jats:italic>\n                      and\n                      <jats:italic>APOE3\/3<\/jats:italic>\n                      mice treated intraperitoneally with D\u2010enantiomer of 4F (D4F) or vehicle for 12\u00a0weeks from 10 to 13 months of age.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      <jats:italic>APOE4\/4<\/jats:italic>\n                      mice showed widespread transcriptomic and lipidomic alterations, including downregulation of lipid metabolism and synaptic pathways, increased ceramides, sphingomyelins, and cholesteryl esters, with decreased diglycerides and triglycerides. D4F treatment shifted relevant gene expression and lipid profiles toward\n                      <jats:italic>APOE3\/3<\/jats:italic>\n                      levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      These findings reveal molecular mechanisms underlying\n                      <jats:italic>APOE4<\/jats:italic>\n                      \u2010driven dysregulation and support the therapeutic potential of HDL\u2010mimetic peptides to mitigate\n                      <jats:italic>APOE4<\/jats:italic>\n                      \u2010associated alterations in AD.\n                    <\/jats:p>\n                  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