Microglial heterogeneity in neurological disorders: From dynamic states to druggable targets

Once viewed as a homogenous population, microglia are now understood to exist as a dynamic continuum of functionally distinct states whose existence is supported by accumulating evidence from multiple experimental approaches. This heterogeneity, spanning molecular, morphological, and metabolic dimensions, is actively sculpted by brain region, life stage, and a complex microenvironment of neuronal, astrocytic, and systemic signals. In neurological disorders such as Alzheimer's disease, this plasticity leads to context-dependent diversification into discrete subsets-ranging from protective, phagocytic phenotypes to detrimental, inflammatory ones-that critically influence disease progression. Decoding this heterogeneity through single-cell and spatial omics provides a new pharmacological blueprint: it reveals key druggable nodes (e.g., TREM2, CD14) that govern pathogenic state transitions and informs the rational design of subset-selective delivery systems (e.g., ligand-directed nanocarriers). However, translating these insights requires overcoming persistent challenges, including species differences between mouse and human microglia, a lack of tools for causal subset manipulation, and the integration of spatial with temporal dynamics. By framing microglial heterogeneity as a central targetable axis, this review outlines a pathway for developing precise, state-modulating therapeutics to intervene in neurodegeneration and neuroinflammation.