Combinatorial Perturbation with Multi-Omics Readout to Dissect Etiology of Alzheimer's Disease Using Stem Cell and In Vivo Models

Combinatorial Perturbation with Multi-Omics Readout to Dissect Etiology of Alzheimer's Disease Using Stem Cell and In Vivo Models Abstract Alzheimer's disease (AD) is a prevalent age-related neurodegenerative disorder. While early-onset AD is driven by well-characterized genes, the mechanistic links between aging and late-onset AD remain elusive. Human genetic studies have revealed numerous risk alleles that modulate AD susceptibility, but their complex interactions are challenging to study using current tools. We propose to develop Combo-Seq/Tag, a powerful toolkit combining precisely installing multiple risk alleles (Combo-Seq) with a multiplex protein tagging tool (Combo-Tag) for studying endogenous protein interactions. These tools will enable efficient perturbation of AD risk genes and multi-omics readouts in human stem cell models. We will also generate a Combo-Seq/Tag mouse strain compatible with the 5xFAD AD model for in vivo study. Our project will yield innovative products, including multiplex, optimized gene-editing vectors, and rich multi-omics datasets, amplifying the impact of AD human genetics studies. By providing a toolkit to dissect the complex genetic interactions underlying AD pathogenesis, our work will contribute to understanding the mechanistic links between aging and neurodegeneration, potentially revealing novel targets for AD diagnosis and therapy.