The Spectrum of Microglia: Decoding Heterogeneity and Plasticity for Therapeutic Gain in Neurological Disorders

Microglia, the resident immune cells of the central nervous system (CNS), have critical roles in brain homeostasis and the pathogenesis of neurological diseases. The conventional M1/M2 classification is currently considered inadequate for describing the complex spectrum of microglial functions. A more accurate model describes microglia as dynamic cells existing along a spectrum of activation states that depend on specific contexts. This review synthesizes current understanding of the microglial spectrum, exploring the diverse phenotypes and functional states that microglia assume across development; aging; and various neurological disorders, including Alzheimer’s disease, Parkinson’s disease, and depression. We subsequently review the essential role of multi-omics technologies, particularly single-cell and spatial omics, which, alongside in vivo imaging, have been instrumental in driving the paradigm shift toward a dynamic microglial model. Furthermore, we summarize the core regulatory mechanisms—spanning genetic, epigenetic, and environmental factors—that shape these distinct microglial phenotypes. We additionally discuss current and emerging therapeutic strategies designed to modulate microglial activity, including pharmacological interventions and cell reprogramming. Finally, we discuss the therapeutic potential of precisely modulating microglial states—a promising direction for developing future precision therapies for neurological disorders.