TREM2

TREM2 (triggering receptor expressed on myeloid cells 2) is a single-pass transmembrane receptor expressed almost exclusively by microglia in the brain. It senses anionic lipids, apolipoproteins and amyloid-beta, signalling through the adaptor DAP12 to drive a transcriptional shift from homeostatic microglia toward the disease-associated microglia (DAM) state, with downstream effects on phagocytosis, lipid metabolism, survival and plaque containment. The rare missense variant R47H (rs75932628) is associated with an approximately 2- to 3-fold increased risk of late-onset Alzheimer disease in pooled analyses, and homozygous loss-of-function variants cause Nasu-Hakola disease. Soluble TREM2 in cerebrospinal fluid is being explored as a biomarker of microglial activation; TREM2 agonist antibodies entered clinical trials, but the lead candidate AL002 (Alector) missed its primary endpoint in the Phase 2 INVOKE-2 trial in early-AD patients in late 2024 and the therapeutic strategy is being reassessed. TREM2 is a key node linking innate immunity to amyloid and tau pathology.