Epigenomic, transcriptional and cellular dissection of Alzheimer's variants

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Abstract The search for effective treatments for Alzheimer's disease (AD), the leading cause of late-onset dementia, has proven challenging. While recent successes in identifying more than a dozen new genes contributing to late-onset or sporadic AD (sAD) have generated considerable excitement in AD research, it is clear from large population studies including GWAS and whole-exome sequencing projects that many single nucleotide polymorphisms (SNPs) contributing to elevated sAD risk reside in non-coding intragenic or regulatory regions. The biological significance of these noncoding SNPs with respect to sAD pathogenesis is not clear. In the current application, we propose a scalable discovery platform for discerning which AD risk SNPs are associated with functional enhancers in specific neural cell types derived from human induced stem cells (hIPSCs). These hIPSCs, created from fibroblasts of sAD patients with a wealth of phenotypes that clearly lead to AD heterogeneity, will enable us to obtain a high-resolution map of AD risk SNPs associated with enhancers and their putative target genes in varied cell types. We will utilize CRISPR/Cas9/dCas9 technologies to directly determine the cell biological consequences of these AD risk genomic variants via 2D and 3D cytosystems. Our comprehensive strategy will identify novel genetic elements and unexpected regulatory pathways contributing to AD pathogenesis and progression that will lead to new therapeutic avenues.