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Spatial and single cell transcriptomics in the human Entorhinal Cortex across diverse risk of Alzheimer’s disease

ABSTRACT: We present the first spatially-resolved transcriptomics and single-nucleus RNA-sequencing integrated dataset from the entorhinal cortex (ERC) of postmortem human brain donors. ERC is implicated in early progression of Alzheimer’s Disease (AD) and we chose this brain region to study gene expression changes associated with AD risk by comparing APOE E2 and E4 allele carriers. Donors with no AD diagnosis or widespread neurodegeneration were exclusively selected. As AD risk is increased in African Ancestry in contrast to European Ancestry backgrounds, and AD risk is also increased in women compared to men, our dataset included donors from these different backgrounds. We identified a pre-myleinating oligodendrocyte sub-cluster with transcriptomic changes strongly associated with APOE E4 carriers. These changes were present in both ancestry backgrounds, although they were more pronounced in African Ancestry donors. To facilitate future studies based on this dataset, we provided the raw and processed data, and created interactive web applications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308007 | GEO | 2025/11/14

REPOSITORIES: GEO

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Project description:Cerebrovascular dysfunction is a hallmark feature of Alzheimer's disease (AD). One of the greatest risk factor for AD is the apolipoprotein E4 (E4) allele. APOE4 genotype has been shown to negatively impact on perivascular amyloid clearance, however, its direct influence along with the other APOE variants (APOE2 and APOE3) on the molecular integrity of the cerebrovasculature has not been largely explored. To address this, we employed a 10-plex tandem isobaric mass tag approach in combination with an ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method, to interrogate unbiased proteomic changes in cerebrovessels from AD and healthy control brains on different APOE genotype backgrounds. We first interrogated changes between healthy control homozygote E2/E2, E3/E3 and E4/E4 cases to identify underlying genotype specific effects on cerebrovessels. EIF2 signaling, regulation of eIF4 and 70S6K signaling and mTOR signaling were the top significantly altered pathways in E4/E4 compared to E3/E3 cases. EIF2, nitric oxide and sirtuin signaling pathways were the top significantly altered pathways in E4/E4 compared to E2/E2 cases. We used a Two-way ANOVA analysis to identify AD-dependent changes and their interactions with APOE genotype. The highest number of significantly regulated proteins from this interaction was observed in E3/E4 (192) and E4/E4 (189) cases. As above, EIF2, mTOR signaling and eIF4 and 70S6K signaling were the top three significantly altered pathways in E4 allele carriers (i.e. E3/E4 and E4/E4 genotypes). Of all the cerebrovascular cell specific markers identified in our proteomic analyses, endothelial cell, astrocyte, and smooth muscle cell specific protein markers were significantly altered in E4/E4 cases, while endothelial cells and astrocyte specific protein markers were altered in E3/E4 cases. These proteomic changes provide novel insights to explain the longstanding link between APOE4 and cerebrovascular dysfunction. The early and converging APOE4 dependent changes we identified could provide novel targets in the cerebrovasculature for developing disease modifying strategies to mitigate the effects of APOE4 genotype on increasing the risk for, and the path towards AD pathogenesis.

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Spatial and single cell transcriptomics in the human Entorhinal Cortex across diverse risk of Alzheimer’s disease

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