PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a leading cause of dementia among the elderly and the most prevalent age- related neurodegenerative disease, affecting ~56 million individuals worldwide. Despite of its high heritability (estimates ranging 60-80%) and many genetic variants (residing in tens of loci across the genome) identified from genome-wide association studies (GWAS), our knowledge of the underlying genetic mechanisms remains limited. Uncovering pathophysiological mechanisms underlying AD proves to be highly challenging. To advance our mechanistic understanding of AD, we will first acquire and harmonize various in-house, protected and public data, encompassing bulk and single cell RNA-seq data, GWAS summary statistics, array genotyping and whole genome sequencing data, as well as functional genomic data. We will then analyze them using a suite of computational methods and bioinformatics tools to generate cell-type-specific mechanistic hypotheses. These hypotheses will be validated through experimental technologies. Our validations will be carried out in iPSC-derived neural cells (particularly excitatory neurons and microglia), as well as in iPSC-derived brain organoids involving diverse cell types including neurons, astrocytes, and microglia. In these iPSC-derived cells and organoids models, we will leverage CRISPRi as well as knock-in experimental technologies to perturb the most promising putatively causal regulatory DNA elements, and evaluate the impact by measuring a cascade of molecular and cellular phenotypes including gene expression and AD related physiological phenotypes.