PLCG2 signaling and genetic resilience in Alzheimer's disease.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and pathological hallmarks, including amyloid plaques, tau tangles, microgliosis, and chronic neuroinflammation. Over the past decade, advances in human genetics have revealed microglia and the innate immune pathways are central determinants of AD susceptibility, resilience, and progression, fundamentally redefining the recent conceptual framework of AD research. Genome-wide association studies (GWAS) implicate microglia-enriched genes including triggering receptor expressed on myeloid cells 2 (TREM2), phospholipase-C gamma 2 (PLCG2), and inositol polyphosphate-5-phosphatase D (INPP5D). Among these, the rare PLCG2 P522R variant is associated with reduced AD risk, enhanced microglial responsiveness, and enrichment in cognitively healthy centenarians. Single-cell and spatial transcriptomic studies have uncovered substantial microglial heterogeneity and pronounced region-specific alterations across age and disease progression. These analyses show that microglia transition through a spectrum of transcriptionally distinct states regulated by coordinated remodeling of lipid metabolic, phagocytic and lysosomal pathways, as well as cytokine-receptor signaling networks. Depending on the direction of these state transitions, microglia may engage neuroprotective programs that enhance debris clearance, maintain tissue homeostasis, and support repair, or alternatively, enter maladaptive states characterized by defective lipid processing, chronic inflammatory signaling, and heightened neurotoxicity. Here, we review genetic, molecular, and pharmacological evidence supporting PLCG2 as a compelling therapeutic target in AD. We integrate insights from transcriptomic and structural analyses, iPSC-derived microglia, and in vivo models that show how PLCG2 modulates microglial states, promotes brain resilience, and mitigates AD-related pathophysiology. We also highlight recent progress in identifying small-molecule PLCG2 activators via high-throughput lipid-vesicle assays and affinity-selection mass spectrometry. Collectively, these multidisciplinary advances position PLCG2 as a genetically validated, mechanistically tractable, and pharmacologically actionable target for precision immune-modulation strategies aimed at preserving cognition and enhancing resilience in brain aging and AD.