Genetic regulation of microglial function in Alzheimer’s disease: Mechanisms and therapeutic implications

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder in which neuroinflammatory and immune mechanisms are increasingly recognised as central drivers of disease onset and progression. Among the brain’s immune cells, microglia have emerged as critical regulators of amyloid and tau pathology, synaptic integrity, and neuronal survival. Compelling human genetic studies reveal that many AD risk loci are enriched in microglia-expressed genes, highlighting microglia not just as responders to neurodegeneration, but as active mediators of genetic susceptibility. This review explores how genetic variation shapes microglial function in AD, focusing on key pathways that govern immune sensing, phagocytosis, intracellular degradation, and inflammatory signaling. Risk-associated variants in genes such as apolipoprotein E (APOE), Triggering Receptor Expressed on Myeloid cells 2 (TREM2), and Cluster of Differentiation 33 (CD33), along with regulators of autophagy and inflammasome activity, influence the balance between protective and maladaptive microglial responses at different stages of disease. Advances in single-cell and spatial transcriptomics have revealed the remarkable heterogeneity of microglial states, challenged traditional binary models of activation, and underscored the need for gene-centered conceptual frameworks. By integrating genetics with functional and systems-level perspectives, this review emphasizes how understanding microglial genetic programs can guide precision-targeted interventions, improve risk stratification, and inspire novel disease-modifying therapies. Ultimately, a genetics-driven approach to microglial regulation provides a strategic roadmap for translating molecular insights into actionable therapeutic advances in AD.