Neurodegenerative disorders, including Alzheimer's disease (AD) and Pick's disease (PiD), are characterized by the accumulation of tau-positive inclusions within neurons or glial cells. These tauopathies exhibit distinct tau isoform profiles, with primary tauopathies such as PiD predominantly featuring 3R tau, while secondary tauopathies like AD involve both 3R and 4R isoforms. Recent scientific investigations have uncovered the impact of tau alterations, including overexpression and hyperphosphorylation, on chromatin structure. In this study, we present a comprehensive analysis of epigenomic changes in the human brain afflicted by AD and PiD at a single-nucleus resolution. We employed single-nucleus ATAC-seq (10x Genomics) on pre-frontal cortex samples from individuals with AD, PiD, and respective control groups (n=8-12/group). Utilizing state-of-the-art Signac and ArchR pipelines, we performed peak-calling and downstream processing, with a specific focus on candidate cis-regulatory elements (cCREs) using the Cicero algorithm. Moreover, we leveraged our dataset to predict an unidentified human-enhancer associated with a critical GWAS gene, shedding light on disease biology. Our analysis incorporated UMAP dimensionality reduction and Leiden clustering of batch-corrected epigenomic data, revealing distinct cell-type clusters among the 198,722 nuclei analyzed in single-nucleus ATAC-seq. In addition, we conducted a genome-wide fine-mapping of GWAS variants for AD and frontotemporal dementia (FTD), offering valuable insights for the functional validation of non-coding GWAS variants and a deeper understanding of disease pathophysiology. Our investigation unveiled both shared and unique changes in open chromatin landscapes in AD and PiD, helping us understand these tauopathies better.