Title: Single nuclei network analyses reveal chromatin accessibility and transcriptomic perturbations in late-stage Alzheimer’s disease
Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by marked alterations in the transcriptome and the chromatin accessibility landscape. Here we probe underlying molecular and genetic mechanisms of AD using a multi -omic approach encompassing RNA and chromatin accessibility assays at the tissue and single nucleus levels in order to compare healthy tissue to late stage AD in the human prefrontal cortex. We profiled ~200k single nuclei to identify transcriptional and epigenomic cell-states enriched in AD samples, and characterize these states along biological trajectories in pseudotime. We construct gene co-expression networks as well as chromatin co-accessibility networks in key neuronal and glial cell types, as well as identify networks that are specific to disease states. We leverage chromatin accessibility of gene promoter sequences to construct a human AD cell atlas encompassing gene expression as well as chromatin features simultaneously. We investigate alterations in co-accessibility networks near AD specific risk variants as defined by genome wide association studies (GWAS). In addition to validating known cell-type perturbations due to AD, at both the chromatin and transcriptome level, we observe disturbances in oligodendrocyte populations that have not previously been implicated in AD.