Growing recognition of the pivotal role microglia play in neurodegenerative and neuroinflammatory disorders has accentuated the need to characterize their function in health and disease. Studies in mouse have applied transcriptome-wide profiling of microglia to reveal key features of microglial ontogeny, functional profile, and phenotypic diversity. While similar, human microglia exhibit clear differences to their mouse counterparts, underlining the need to develop a better understanding of the human microglial profile. On examining published microglia gene signatures, limited consistency was observed between studies. Hence, we sought to derive a core microglia signature of the human central nervous system (CNS), through a comprehensive analysis of existing transcriptomic datasets. Nine datasets derived from cells and tissues, isolated from various regions of the CNS across numerous donors, were subjected independently to an unbiased correlation network analysis. From each dataset, a list of coexpressing genes corresponding to microglia was identified, with 249 genes highly conserved between them. This core signature included known microglial markers, and compared with other signatures provides a gene set specific to microglia in the context of the CNS. The utility of this signature was demonstrated by its use in detecting qualitative and quantitative region-specific alterations in aging and Alzheimer's disease. These analyses highlighted the reactive response of microglia in vulnerable brain regions such as the entorhinal cortex and hippocampus, additionally implicating pathways associated with disease progression. We believe this resource and the analyses described here, will support further investigations to the contribution of human microglia in CNS health and disease.