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However, therapeutic strategies targeting lipid pathways remain largely unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      The therapeutic potential of PLA2G4E, previously identified in our earlier work, was validated in the APP\n                      <jats:sup>NL\u2010G\u2010F<\/jats:sup>\n                      AD mouse model using a translational gene\u2010delivery approach with a blood\u2013brain barrier\u2013penetrant adeno\u2010associated vector (AAV) (AAVP31) to achieve widespread brain expression. Brain lipidomics was performed to investigate the molecular mechanisms underlying treatment effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>PLA2G4E expression rescued memory deficits, reduced tau phosphorylation, and improved brain glucose metabolism and cognitive performance in AD models and aged wild\u2010type mice. These effects were accompanied by partial normalization of disease\u2010associated lipid metabolic alterations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>These findings support PLA2G4E as a promising therapeutic target in AD and provide mechanistic evidence linking modulation of lipid metabolic pathways to synaptic and cognitive rescue.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.70285","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T05:51:12Z","timestamp":1783317072000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reprogramming lipid metabolism for cognitive restoration in Alzheimer's via PLA2G4E"],"prefix":"10.1002","volume":"12","author":[{"given":"Sara","family":"Badesso","sequence":"first","affiliation":[{"name":"Gene Therapy for CNS 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