Pathologically Late onset Alzheimer’s disease (AD) is characterized by extracellular amyloid plaques composed by aggregated Amyloid b and intracellular neurofibrillary tangles made of hyperphosphorylated TAU protein (encoded by MAPT gene). Recently, it has been shown that in human and mouse brain, tau co- immunoprecipitated with proteins and small RNAs that play a key role in in RNA modification and pre-mRNA splicing. It has been shown that cytosolic and nuclear tau aggregates are enriched for small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs) including SNORD115 and SNORD116 families of C/D box snoRNAs. Our preliminary data demonstrate a significant effect of Braak stage on expression level of snoRNAs and snRNAs in brain samples from AD patients as compared to controls. We also show that insoluble tau in AD but not control brains co-immunoprecipitated with selective snoRNAs of C/D box (SNORDs) but not H/A box (SNORA). We hypothesize that tau aggregates bind to snoRNAs and snRNAs and affect their traffic between the nucleus and cytoplasm. snoRNAs, snRNAs and hyperphosphorylated Tau in Tau-RNA complexes lose their physiological function in RNA processing and chromatin remodeling thus affecting chromatin accessibility and gene expression. This proposal's primary goal is to explore and demonstrate that selective regional vulnerability in AD brain and incremental hierarchical spreading of hyperphosphorylated Tau and deposition of NFT are associated and interconnected with changes in gene expression and chromatin architecture. We will achieve the goal by interrogating 3 distinct anatomical brain regions at different Braak stages from human subjects and animal models. Specific Aim 1: To conduct epigenomic and transcriptomic profiling across brain samples at different Braak stages and to detect tangle-specific changes in gene expression and chromatin structure. We will answer the question how NFT burden affects chromatin accessibility and gene expression. Specific Aim 2: To reveal a perturbed transcriptional control of SNORDs hosted on SNURF-SNRPN/UBE2A region on human Chr15 and to correlate their expression with the progression of AD tau pathology. We will identify snoRNAs and snRNAs bound to insoluble Tau aggregates and changes in methylation status within Chr15q11- q13 locus that affect transcriptional activity of SNURF-SNRPN domain. Specific Aim 3: Using AD mouse models to reveal the effect of hyperphosphorylated Tau and NFT on plasma, and brain-derived extracellular vesicles’ cargo. We will use PS19 mouse model and examine the effect of tau pathology in different age groups on the enrichment of snoRNA secreted in extracellular vesicles from brain, ISF, CSF and plasma.