Zhang, XiaolingFarrer, Lindsay A.O'Neill, Nicholas Kerry2024-12-182025https://hdl.handle.net/2144/495542025Alzheimer’s disease (AD) is a progressive and complex neurodegenerative disorder characterized by increasing amyloid-β (Aβ) plaque burden, followed by increasing neurofibrillary tau tangles (NFT) and cognitive decline. However, many individuals fall outside of this typical progression, either exhibiting NFTs without Aβ or maintaining cognitive performance despite the presence of AD pathology, i.e., cognitive resilience. AD progression is also associated with changes in cell-type abundance and cell-type-specific activity. This dissertation investigates these topics by integrating AD brain single-nuclei RNA-seq (snRNA-seq) with large-scale bulk RNA-seq datasets and whole genome sequencing datasets generated from the same individuals. We developed an algorithm for bulk cell-type deconvolution using a snRNA-seq reference dataset by adjusting for technical differences specific to snRNA-seq. We then applied this algorithm to examine the relationship between cell-type abundance and AD endophenotypes, including cognitive resilience, in brain regions that are vulnerable or resistant to the disease. In addition, we identified and discussed genetic drivers of changes in cell-type abundance. Finally, we generated highly cell-type-specific AD polygenic risk scores (ct-ADPRS) to investigate the relationship between cell-type activity and AD progression.en-USBioinformaticsDeconvolutionNPYSingle-nucleiTMEM106BThesis/Dissertation2024-12-170000-0002-9953-9940