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This study investigated APOE4 proteome changes in people with AD, mild cognitive impairment, and no impairment. Clinical, APOE genotype, and cerebrospinal fluid (CSF) proteome and AD biomarker data was sourced from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Proteome profiling was done using supervised machine learning. We found an APOE4\u2010specific proteome signature that was independent of cognitive diagnosis and AD pathological biomarkers, and increased the risk of progression to cognitive impairment. Proteins were enriched in brain regions including the caudate and cortex and cells including endothelial cells, oligodendrocytes, and astrocytes. Enriched peripheral immune cells included T cells, macrophages, and B cells. APOE4 carriers have a unique CSF proteome signature associated with a strong brain and peripheral immune and inflammatory phenotype that likely underlies APOE4 carriers' vulnerability to cognitive decline and AD as they age.<\/jats:p>","DOI":"10.1111\/acel.14439","type":"journal-article","created":{"date-parts":[[2024,12,25]],"date-time":"2024-12-25T23:57:12Z","timestamp":1735171032000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Proteome profiling of cerebrospinal fluid using machine learning shows a unique protein signature associated with\n                    <scp>APOE4<\/scp>\n                    genotype"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0592-984X","authenticated-orcid":false,"given":"Artur","family":"Shvetcov","sequence":"first","affiliation":[{"name":"Translational Dementia Research Group, Centre for Immunology and Allergy Research Westmead Institute for Medical Research  Sydney NSW Australia"},{"name":"Department of Psychological Medicine Sydney Children's Hospital Network  Sydney NSW Australia"},{"name":"Discipline of Psychiatry and Mental Health, School of Clinical Medicine, Faculty of Medicine and Health University of New South Wales  Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"Thomson","sequence":"additional","affiliation":[{"name":"Translational Dementia Research Group, Centre for Immunology and Allergy Research Westmead Institute for Medical Research  Sydney NSW Australia"},{"name":"School of Medical Sciences, Faculty of Medicine and Health The University of Sydney  Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann\u2010Na","family":"Cho","sequence":"additional","affiliation":[{"name":"Human Brain Microphysiology Systems Group, School of Biomedical Engineering, Faculty of Engineering The University of Sydney  Sydney NSW 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