Elucidate the roles of Alzheimer's disease risk genes and variants in gene expression and AD-related phenotypes

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Project Summary/Abstract AD is an age-related neurodegenerative disorder affecting 10% of the population over 65. The genetics of Late- onset AD (LOAD) is complex. Multiple common variants usually influence LOAD with smaller effect sizes. Whether and how these predicted AD risk genes contribute to AD pathogenesis and which variant affect their expression remain, for the most part, to be characterized. The overarching goal of the proposed study is to provide a comprehensive annotation of roles for AD risk genes and determine AD casual variants contribute to AD via modulating AD-risk gene expression. We will: (1) determine and benchmark the biological consequences of putative AD risk genes identified by genetic analysis using CRISPRi and single-cell RNA-seq in iPSC-derived excitatory neurons, hippocampal dentate granule cells, and microglia. We will also follow up using functional assays in cells and organoids for AD-related phenotypes, (2) characterize enhancers and AD-associated variants for AD risk genes in iPSC-derived hippocampal DG neurons and hippocampal organoids, (3) elucidate the roles of enhancers and AD variants in iPSC-derived excitatory neurons, microglia, and cerebral organoids with microglia. The proposed work will provide a comprehensive annotation of AD risk genes and demystify AD- causal variants affecting gene expression networks and cellular functions related to AD pathogenesis. The success of our proposal will be an essential step towards better risk prediction and new therapeutic targets in AD.