An integrated single-nucleus chromatin accessibility and transcriptome landscape of the human hippocampus with AD

Alzheimer's disease (AD) is the leading cause of dementia globally, with hippocampal atrophy recognized as an early hallmark. However, the epigenetic regulation of transcription within the hippocampus of AD remains elusive. Here, we employed single-nucleus multi-omics sequencing techniques, single-nucleus RNA sequencing and single-nucleus ATAC sequencing, to generate transcriptome profile and chromatin accessibility landscapes in human hippocampus with and without AD. We established peak to gene links in a cell type specific manner and subsequently characterized AD-associated links across hippocampal cell types. Additionally, we constructed transcriptional regulatory networks for microglia and astrocytes, identifying several AD-related transcription factors, such as SPI1 and ATF3 for reactive microglia, and NFE2L2 for reactive astrocyte. By comparing multi-omics data from the hippocampus and prefrontal cortex (PFC) of AD patients, we identified 267 AD-associated genes were shared between hippocampus and PFC. We also characterized 3,108 brain region-specific but AD-associated genes. This finding highlights the substantial variance in epigenetic regulation triggered by AD between the two brain regions in single-cell resolution during AD pathogenesis. Additionally, species comparative analysis revealed that human biased genes identified in non-neurons tended to have more chance to associated with AD than mouse biased genes, underscoring the complexity of pathology and presenting challenges for cross-species translational research in AD. Taken together, our study systematically showed coordinated alteration in the epigenome and transcriptome of hippocampus with AD and thus provided insights to the pathogenesis of AD.