{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:43:10Z","timestamp":1791420190636,"version":"4.3.3"},"posted":{"date-parts":[[2025,11,20]]},"group-title":"Neuroscience","reference-count":139,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Carol and Gene Ludwig Family Foundation"},{"id":[{"id":"https:\/\/ror.org\/04q36wn27","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The entorhinal cortex (ERC) is implicated in early progression of Alzheimer\u2019s disease (AD). Here we investigated the impact of established biological risk factors for AD, including\n                  <jats:italic>APOE<\/jats:italic>\n                  genotype (E2 versus E4 alleles), sex, and ancestry, on gene expression in the human ERC. We generated paired spatially-resolved transcriptomics (SRT) and single-nucleus RNA sequencing data (snRNA-seq) in postmortem human ERC tissue from middle aged brain donors with no history of AD.\n                  <jats:italic>APOE<\/jats:italic>\n                  -dependent changes in gene expression predominantly mapped to a transcriptionally-defined oligodendrocyte subtype, which varied substantially with ancestry, and suggested differences in oligodendrocyte differentiation and myelination. Integration of SRT and snRNA-seq data identified a common gene expression signature associated with\n                  <jats:italic>APOE<\/jats:italic>\n                  genotype, which we localized to the same oligodendrocyte subtype and a white matter spatial domain. This suggests that AD risk in ERC may be associated with disrupted oligodendrocyte function, potentially contributing to future neurodegeneration.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Lay Summary<\/jats:title>\n                  <jats:p>\n                    Alzheimer\u2019s disease (AD) is a neurodegenerative disorder that accounts for 60-80% dementia cases. Apolipoprotein E (\n                    <jats:italic>APOE)<\/jats:italic>\n                    genotype is the strongest genetic risk factor for AD, and the entorhinal cortex (ERC) is a brain region implicated in its earliest progression. Our study investigated how\n                    <jats:italic>APOE<\/jats:italic>\n                    genotype impacts gene expression in the ERC. We identified genotype-dependent effects on oligodendrocytes with different transcriptional profiles related to maturation that may help explain how\n                    <jats:italic>APOE<\/jats:italic>\n                    genotype mediates its effects on AD risk.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.20.689483","type":"posted-content","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T02:20:11Z","timestamp":1763691611000},"source":"Crossref","is-referenced-by-count":4,"title":["<i>APOE<\/i>\n                  E4 Alzheimer\u2019s Risk Converges on an Oligodendrocyte Subtype in the Human Entorhinal Cortex"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5148-3602","authenticated-orcid":false,"given":"Louise 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