Alzheimer?s disease (AD) is now a global health crisis, with AD-associated costs in the U.S. alone expected to exceed $1 trillion by 2050. Due to the growing aging population and lack of effective treatments, there is an urgent need to improve our understanding of the causes and pathogenesis of the disease. Interestingly, while >95% of AD cases are sporadic (sAD) and thus have no known cause, sAD displays high (~60-80%) heritability, and genome-wide association studies (GWAS) have identified >20 genomic loci that affect sAD risk, strongly implicating genetic risk factors in sAD pathogenesis. Several lines of evidence suggest that many GWAS risk loci affect disease risk through cell type-specific effects on gene expression. However, difficulties in 1) interpreting the functions of the non-coding genome (in which >90% of disease- associated risk variants reside) and 2) generating physiologically-relevant human brain cell types with which to model human brain disease have impeded progress in the mechanistic interrogation of these loci. In order to address these issues, this proposal will combine state-of-the-art functional genomics approaches with human induced pluripotent stem cell (hiPSC) technology in order to determine the role of sAD genetic risk loci in sAD pathogenesis. Epigenomic and transcriptomic profiling of genetically-matched brain- and hiPSC-derived neurons, astrocytes, oligodendrocytes and microglia will identify the active genes, cis-regulatory elements, and enhancer/promoter interactions in each cell type, without the confounding variable of inter-individual variation, and will facilitate the prioritization and functional dissection of sAD risk loci. At three prioritized loci, epigenome editing and precise genome editing will be performed to determine the causal sAD risk variants and their target genes. Isogenic hiPSC lines will then be used to investigate the effects of these variants on known sAD- relevant cellular phenotypes, including amyloid ? and tau levels and pathology, amyloid ? fibril-induced toxicity, neuronal excitotoxicity, phagocytosis of amyloid ? fibrils by astrocytes and microglia, and glial-dependent effects on neuronal viability. Finally, gene set enrichment analyses will be performed to identify cellular pathways that are disrupted sAD causal risk variants in an unbiased manner, which will inform future experiments and may identify potential therapeutic targets. In summary, this proposal will functionally dissect the mechanisms underlying sAD risk loci in order to identify novel sAD-related genes and pathways for downstream therapeutic development.

Public Health Relevance

Alzheimer?s disease is a global health crisis, with costs expected to reach $1 trillion by 2050 in the U.S. alone. More than twenty regions of the human genome are known to affect risk for Alzheimer?s, but the genes affected in these regions are almost entirely unknown. This proposal will identify these risk genes and their roles in Alzheimer?s disease, and therefore will identify new potential therapeutic targets.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Wise, Bradley C
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Whitehead Institute for Biomedical Research
United States
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