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The APOE3 allele is risk-neutral, the APOE4 allele increases the risk of developing AD, and the APOE2 allele is neuroprotective. Methods: We utilized RNA sequencing of hemi-brains from a mouse model homozygous for each of these humanized APOE alleles to study gene expression profiles between mice aged 12 months of age (MO) and 18 MO, independent of \u03b2-amyloid and tau pathology. Results: More than half of the differentially expressed genes (DEGs) within each genotype were shared with at least one other APOE allele, including 1610 DEGs that were shared across the three genotypes. These DEGs represent changes driven by aging rather than APOE genotype. Aging induced DEGs and biological pathways involving metabolism, synaptic function, and protein synthesis, among others. Alterations in these pathways were also identified by DEGs unique to APOE4, suggesting that the APOE4 allele drives the aging phenotype. In contrast, fewer pathways were identified from DEGs unique to APOE2 or APOE3. Conclusions: Transcriptomic results suggest that the most significant impact on brain-level expression changes in humanized APOE mice is aging and that APOE4 exacerbates this process. These in vivo findings within an established model system are consistent with brain aging being the greatest risk factor for AD and suggest that APOE4 expression promotes an aging phenotype in the brain that interacts with, and contributes to, aging-driven AD risk. Results reinforce the impact age and APOE allele contribute to AD and age-related neurodegeneration, and foster greater mechanistic understanding as well as inform therapeutic intervention.<\/jats:p>","DOI":"10.3390\/brainsci15101117","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T07:33:50Z","timestamp":1760686430000},"page":"1117","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Aging, Rather than Genotype, Is the Principal Contributor to Differential Gene Expression Within Targeted Replacement APOE2, APOE3, and APOE4 Mouse Brain"],"prefix":"10.3390","volume":"15","author":[{"given":"Amanda","family":"Labuza","sequence":"first","affiliation":[{"name":"Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA"},{"name":"Department of Psychiatry, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0862-0883","authenticated-orcid":false,"given":"Harshitha","family":"Pidikiti","sequence":"additional","affiliation":[{"name":"Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5701-0694","authenticated-orcid":false,"given":"Melissa J.","family":"Alldred","sequence":"additional","affiliation":[{"name":"Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA"},{"name":"Department of Psychiatry, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyrillos W.","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1968-4310","authenticated-orcid":false,"given":"Katherine Y.","family":"Peng","sequence":"additional","affiliation":[{"name":"Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA"},{"name":"Department of Psychiatry, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Pasato","sequence":"additional","affiliation":[{"name":"Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2836-6683","authenticated-orcid":false,"given":"Adriana","family":"Heguy","sequence":"additional","affiliation":[{"name":"Genome Technology Center, New York University Grossman School of Medicine, New York, NY 10016, USA"},{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Mathews","sequence":"additional","affiliation":[{"name":"Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA"},{"name":"Department of Psychiatry, New York University Grossman School of Medicine, New York, NY 10016, USA"},{"name":"NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1797-4288","authenticated-orcid":false,"given":"Stephen D.","family":"Ginsberg","sequence":"additional","affiliation":[{"name":"Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA"},{"name":"Department of Psychiatry, New York University Grossman School of Medicine, New York, NY 10016, USA"},{"name":"NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY 10016, USA"},{"name":"Department of Neuroscience & Physiology, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1007\/s00109-016-1427-y","article-title":"Apolipoprotein E: From cardiovascular disease to neurodegenerative disorders","volume":"94","author":"Mahley","year":"2016","journal-title":"J. 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