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Emerging evidence suggests that ApoE4 increases AD risk by disrupting microglial metabolism and function. However, whether ApoE lipidation state contributes to microglial dysfunction remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>Human microglia were treated with lipid\u2010free (LF) or lipid\u2010bound ApoE3 or ApoE4. Label\u2010free, live\u2010cell holotomography and global proteomics were used to assess isoform\u2010 and lipidation\u2010specific effects on lipid droplet (LD) dynamics, mitochondrial morphology, and microglial phenotype.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>ApoE4 treatment resulted in fewer but enlarged LDs and increased mitochondrial fragmentation compared to ApoE3, effects that were enhanced by lipid\u2010bound ApoE4. Proteomic analyses revealed a strong type I interferon response in cells exposed to LF\u2010ApoE, which was exacerbated by LF\u2010ApoE4.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>These findings indicate that lipid\u2010bound ApoE4 drives metabolic reprogramming, whereas LF\u2010ApoE4 promotes inflammatory signaling, identifying ApoE lipidation as a critical modifier of ApoE4\u2010associated AD risk.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71882","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T03:03:58Z","timestamp":1791774238000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ApoE lipidation state directs immunometabolic reprogramming of human 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