TREM2 as a central immunometabolic hub in Alzheimer's disease: linking microglial states, lipid stress, and disease-stage-specific intervention.

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a crucial role in regulating microglial function in Alzheimer's disease (AD) and other neurodegenerative disorders. Genetic studies have identified rare coding variants in TREM2 as significant risk factors for late-onset AD (LOAD), highlighting the importance of disrupted microglial signaling in disease pathogenesis. Biochemically, TREM2 acts as a receptor for lipid- and damage-associated molecular patterns, recognizing anionic phospholipids, myelin-derived lipids, apolipoproteins, and aggregated amyloid-β (Aβ). It engages with adaptors like DAP12 and DAP10, activating key signaling pathways, including SYK, PI3K-AKT-mTOR, and PLCγ2, leading to microglial transcriptional and metabolic reprogramming. These processes are essential for the transition of microglia to disease-associated microglia (DAM), influencing amyloid plaque compaction and tau pathology propagation. This review aims to synthesize the latest insights into TREM2 biology, focusing on the role of TREM2 in microglial state transitions, lipid metabolism, and myelin turnover. It also examines the pathophysiological relevance of soluble TREM2 (sTREM2) and AD-associated TREM2 variants. Furthermore, the review explores the therapeutic potential of targeting TREM2, including strategies based on agonistic antibodies and modulation of receptor shedding. Beyond prior descriptive summaries, we organize these findings within a stage-resolved immunometabolic framework that links disease timing, lipid-stress context, and microglial state transitions. This framework is intended to explain why similar TREM2-directed interventions may yield different outcomes across disease stages and pathology compositions. We further highlight stage-specific translational logic, including biomarker-informed (e.g., sTREM2-guided) stratification and monitoring, to support testable and clinically actionable trial designs.