Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease

Recent human genetic studies revealed that Alzheimer's disease risk loci are enriched in genes expressed in myeloid cells, including microglia, the brain's resident immune cells. Notably, several risk-associated genes, such as SPI1 and MEF2C, encode transcription factors (TFs) that control critical microglial functions, including phagocytosis, inflammatory responses, and neurotrophic support. The objective of this article is to review the recent progress in understanding these TFs and evaluate them as therapeutic targets rather than as markers of microglial state. We examine the genetic evidence implicating PU.1, MEF2C, IRF8, and BHLHE40/41, the in vivo evidence from animal models, the transcriptional network these factors regulate, and the barriers to clinical translation. Because these TFs orchestrate broad gene expression networks by regulating multiple disease-relevant downstream partners, targeting their expression level or activity could achieve greater therapeutic efficacy than targeting single genes, provided that the dose and disease stage of modulation are carefully considered.