Alzheimer Disease Heterogeneity Explained by Polygenic Risk Scores Derived from Brain Transcriptomic Profiles

INTRODUCTIONAlzheimers disease (AD) is heterogeneous, both clinically and neuropathologically. We investigated whether polygenic risk scores (PRSs) integrated with transcriptome profiles from AD brains can explain AD clinical heterogeneity. METHODSWe conducted co-expression analysis and identified gene-sets (modules) which were preserved in three AD transcriptome datasets and associated with AD-related neuropathological traits for neuritic plaques (NPs) or neurofibrillary tangles (NFTs). We computed the module-based PRS (mbPRS) for each module and tested associations for mbPRSs with cognitive test scores, cognitively-defined AD subgroups, and brain imaging data. RESULTSOf the modules significantly associated with NPs and/or NFTs, the mbPRSs from two modules (M6 and M9) showed distinct associations with language and visuospatial functioning as well as their matching AD-subgroups and brain atrophy at specific regions. DISCUSSIONOur findings demonstrate that polygenic profiling based on co-expressed gene-sets can explain heterogeneity in AD patients, enabling to genetically-informed patient stratification and precision medicine in AD.