bioRxiv : the preprint server for biology · 2025
APOE E4 Alzheimer's Risk Converges on an Oligodendrocyte Subtype in the Human Entorhinal Cortex.
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Huuki-Myers Louise A, Divecha Heena R, Bach Svitlana V, Valentine Madeline R, Eagles Nicholas J, Mulvey Bernard, Bharadwaj Rahul A, Zhang Ruth, Evans James R, Grant-Peters Melissa, Miller Ryan A, Kleinman Joel E, Han Shizhong, Hyde Thomas M, Page Stephanie C, Weinberger Daniel R, Martinowich Keri, Ryten Mina, Maynard Kristen R, Collado-Torres Leonardo
Аннотация
The entorhinal cortex (ERC) is implicated in early progression of Alzheimer's disease (AD). Here we investigated the impact of established biological risk factors for AD, including APOE 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. APOE-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 APOE 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.