Project Summary
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 β and tau levels and pathology, amyloid β fibril-induced toxicity,
neuronal excitotoxicity, phagocytosis of amyloid β 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.