Abstract Microglia have fundamental roles in health and disease, however effects of age, sex and genetic factors on human microglia have not been fully explored. We applied bulk and single cell approaches to comprehensively characterize human microglia transcriptomes and their associations with age, sex and APOE . We identified a novel microglial signature, characterized its expression in bulk tissue and single cell microglia transcriptomes. We discovered microglial co-expression network modules associated with age, sex and APOE -ε4 that are enriched for lipid and carbohydrate metabolism genes. Integrated analyses of modules with single cell transcriptomes revealed significant overlap between age-associated module genes and both pro-inflammatory and disease-associated microglial clusters. These modules and clusters harbor known neurodegenerative disease genes including APOE, PLCG2 and BIN1 . Meta-analyses with published bulk and single cell microglial datasets further supported our findings. Thus, these data represent a well-characterized human microglial transcriptome resource; and highlight age, sex and APOE -related microglial immunometabolism perturbations with potential relevance in neurodegeneration.

Transcriptional landscape of human microglia reveals robust gene expression signatures that implicates age, sex and <i>APOE</i>-related immunometabolic pathway perturbations

Transcriptional landscape of human microglia reveals robust gene expression signatures that implicates age, sex and APOE-related immunometabolic pathway perturbations