Our genetic analyses show that the protective allele at the MS4A locus is associated with lower expression of MS4A4A and MS4A6A in human myeloid cells, and the BV2 experiment demonstrated that lower expression of Spi1 (which is protective in humans) led to lower expression of Ms4a4a and Ms4a6d (mouse ortholog of MS4A6A), which are also associated with reduced AD risk in humans. Transcriptomic and proteomic analyses of microglial cells suggested a microglial homeostatic signature that is perturbed during aging and under pathological conditions48. It will be valuable to test whether genetically altered SPI1 levels prime microglia to exacerbate or alleviate transcriptional responses that occur during aging or disease development. Together with genetic variation in myeloid genes associated with AD as an amplifier, SPI1 may be a master regulator capable of tipping the balance toward a neuroprotective or neurotoxic microglial phenotype.
