Cellular dependency analysis identifies genes implicated in Alzheimer’s disease (AD) as potential treatment targets

Background Genes involved in the progression of Alzheimer’s disease (AD) have been identified, but these genes have not been studied in the context of CRISPR knockouts and RNAi screens to reveal cell‐specific vulnerabilities. Method A list of 105 AD‐associated genes, found through genome‐wide association studies (GWAS) and gene expression network analyses, was compiled. Expression and knock‐down/out dependency data for over 700 cell lines was obtained through the Cancer Dependency Map (DepMap). The expression‐associated dependencies were specifically examined in three tissue types that may be relevant to AD etiology: hematopoietic and lymphoid tissue, central nervous system, and autonomic ganglia. Result SPI1, MEF2C, GAB2, and ABCC11 in hematopoietic and lymphoid tissue cell lines were established as genes of interest since their genetic knockouts specifically affected cells showing high expression of these genes. Other genes exhibiting expression‐associated dependencies include ACTG1 in autonomic ganglia and GLS in central nervous system cell lines. Investigating these genes for expression and dependency patterns in their respective AD tissue of interest highlighted cell lines that had the most significant decrease in cell survival and growth after CRISPR knockout or RNAi screen. Conclusion SPI1, MEF2C, GAB2, and ABCC11 demonstrated expression‐associated dependencies in cell lines of AD‐associated tissues, and present as potential targets for AD.