Single-nucleus chromatin accessibility and transcriptomic characterization of Alzheimer's Disease

The gene-regulatory landscape of the brain is highly dynamic in health and disease, coordinating a menagerie of biological processes across¬ distinct cell-types. Here, we present a multi-omic single-nucleus study of 191,890 nuclei in late-stage Alzheimer's Disease (AD), accessible through our intuitive web portal, profiling chromatin accessibility and gene expression in the same biological samples and uncovering vast cellular heterogeneity. We identified cell-type specific, disease-associated candidate cis-regulatory elements and their candidate target genes, including an oligodendrocyte-associated regulatory module containing links to APOE and CLU. We describe cis-regulatory relationships in specific cell-types at AD risk loci defined by genome wide association studies (GWAS), demonstrating the utility of this multi-omic single-nucleus approach. Trajectory analysis of glial populations identified disease-relevant transcription factors, like SREBF1 and their regulatory targets. Further, we introduce scWGCNA, a co-expression network analysis strategy robust to the sparsity of single-cell data, to perform a systems-level meta-analysis of AD transcriptomics. Overall design: A multi-omics analysis of Alzheimer's Disease in human postmortem brain tissue using single-nucleus ATAC-seq and RNA-seq (bulk and single-nucleus).