Abstract In the post-GWAS era, there is an unmet need to decode the underpinning genetic etiologies of late-onset Alzheimer’s disease (LOAD) and translate the associations to causation. Toward that goal, we conducted ATAC-seq profiling using neuronal nuclear protein (NeuN) sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner. We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions (±100kb of SNP). While the non-neuronal nuclei did not show LOAD-specific differences, stratification by sex identified 842 LOAD-specific chromatin accessibility sites in females. Seven of these sex-dependent sites in the non-neuronal samples overlapped LOAD-GWAS regions including APOE . LOAD loci were functionally validated using single-nuclei RNA-seq datasets. In conclusion, using brain sorted-nuclei enabled the identification of sex-dependent cell type-specific LOAD alterations in chromatin structure. These findings enhance the interpretation of LOAD-GWAS discoveries, provide potential pathomechanisms, and suggest novel LOAD-loci. Furthermore, our results convey mechanistic insights into sex differences in LOAD risk and clinicopathology. GRAPHICAL ABSTRACT

Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer’s disease brains