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Apolipoprotein E4 (APOE4) is a significant genetic risk factor for AD, yet its specific role at the presymptomatic stage is not fully understood. This study aimed to elucidate the cellular and molecular effects of APOE4 compared to APOE3 on AD progression during the presymptomatic stage.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We generated <jats:italic>5xFAD<\/jats:italic> AD mice carrying human APOE3 or APOE4 and their non\u2010AD controls. Behavioral tests, immunostaining, quantitative proteomics and phosphoproteomics, Golgi staining, and Western blotting were conducted at 3 or 10\u2009months of age, respectively. Cell culture experiments were performed to assess APOE4's direct impact on neuronal mitochondrial function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>APOE4 significantly increased \u03b2\u2010amyloid (A\u03b2) deposition and microglial activation compared to APOE3 in <jats:italic>5xFAD<\/jats:italic> mice at the presymptomatic stage, without aggravating the blood\u2013brain barrier disruption. Proteomic and biochemical analysis revealed strong molecular features of synaptic degeneration and mitochondrial dysfunction associated with APOE4. Notably, APOE4 promoted mitochondrial fusion and mitophagy while inhibiting fission, leading to impaired neuronal energy supply and increased reactive oxygen species.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings indicate that APOE4 accelerates AD pathologies at the presymptomatic stage by exacerbating A\u03b2 deposition, neuroinflammation, and synaptic degeneration. The study highlights mitochondrial dysfunction as a critical mediator of APOE4\u2010induced AD progression, providing potential targets for early intervention.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70306","type":"journal-article","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T04:49:01Z","timestamp":1741841341000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Sequential Proteomic Analysis Reveals the Key <scp>APOE4<\/scp>\u2010Induced Pathological and Molecular Features at the Presymptomatic Stage in Alzheimer's Disease Mice"],"prefix":"10.1111","volume":"31","author":[{"given":"Pengju","family":"Wei","sequence":"first","affiliation":[{"name":"State Key Laboratory of Biomedical Imaging Science and System Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences  Shenzhen Guangdong 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