Data integration strategies to study gene expression in Alzheimer's disease

The complexity of the human brain is largely coordinated through multiple layers of transcriptional regulation. This complexity generates functionally distinct RNA molecules with specialized posttranscriptional modifications. In recent years, several studies have profiled transcriptional changes that occur in the Alzheimer's disease (AD) brain. Yet, the underlying genetic mechanisms mediating transcriptional abnormalities in the AD brain have not been thoroughly elucidated. Further, the impact of transcriptional modifications on cognition are also poorly understood. This study will utilize a dataset of 424 human brain cortices profiled by single nucleus RNA sequencing (snRNAseq). This dataset consists of 158 non-neurologic disease controls and 266 AD patients from the ROSMAP cohort. Our preliminary data demonstrate cell-type-specific transcriptional changes in the AD brain. We will leverage this dataset to identify mechanisms mediating transcriptional abnormalities and their impact on cognition. We will further verify RNA transcriptional changes within tissues using spatial transcriptomics in a separate cohort of 20 non-neurologic disease controls and 20 AD patients from UC Irvine. Altogether, this project will determine the mechanisms of genetic regulation on the diverse molecular identities of brain cell types and their influence on cognitive impairment in AD.