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

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. Overall design: We obtained tissue blocks of postmortem human brain entorhinal cortex (ERC) from 31 neurotypical adult brain donors carrying either E2 or E4 APOE alleles from both African and European ancestry. For each donor, a sample was generated for both spatially resolved transcriptomics with 10x Visium, and single nucleus RNA-seq with 10x Chromium. Visium data showed 9 transcriptional distinct spatial domains. snRNA-seq data was clustered into 38 fine subtypes across 8 broad cell types. Differential expression between APOE carrier status (E2+ vs. E4+) was performed at the cluster level in both data types.