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However, there are paradoxical <jats:italic>APOE<\/jats:italic> \u025b4 carriers who remain disease\u2010free and <jats:italic>APOE<\/jats:italic> \u025b2 carriers with LOAD. We compared exomes of healthy <jats:italic>APOE<\/jats:italic> \u025b4 carriers and <jats:italic>APOE<\/jats:italic> \u025b2 Alzheimer's disease (AD) patients, prioritizing coding variants based on their predicted functional impact, and identified 216 genes with differential mutational load between these two populations. These candidate genes were significantly dysregulated in LOAD brains, and many modulated tau\u2010 or \u03b242\u2010induced neurodegeneration in <jats:italic>Drosophila<\/jats:italic>. Variants in these genes were associated with AD risk, even in <jats:italic>APOE<\/jats:italic> \u025b3 homozygotes, showing robust predictive power for risk stratification. Network analyses revealed involvement of candidate genes in brain cell type\u2010specific pathways including synaptic biology, dendritic spine pruning and inflammation. These potential modifiers of LOAD may constitute novel biomarkers, provide potential therapeutic intervention avenues, and support applying this approach as larger whole exome sequencing cohorts become available.<\/jats:p>","DOI":"10.1002\/alz.12240","type":"journal-article","created":{"date-parts":[[2020,12,7]],"date-time":"2020-12-07T08:04:49Z","timestamp":1607328289000},"page":"831-846","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Harnessing the paradoxical phenotypes of APOE \u025b2 and APOE \u025b4 to identify genetic modifiers in Alzheimer's disease"],"prefix":"10.1002","volume":"17","author":[{"given":"Young Won","family":"Kim","sequence":"first","affiliation":[{"name":"Program in Integrative Molecular and Biomedical Sciences Baylor College of Medicine  Houston Texas 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