Synergistic potential of TREM2 agonists and exercise training in Alzheimer’s disease

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-enriched receptor that regulates phagocytosis, lipid metabolism, and inflammation resolution in the brain. Loss or mutation of TREM2, including the R47H variant, impairs amyloid-β clearance and lipid handling, thereby increasing the risk and accelerating the progression of Alzheimer's disease (AD). TREM2 signaling couples debris recognition with mitochondrial activation and fatty acid oxidation, maintaining microglial energy balance and promoting a reparative phenotype. Pharmacologic TREM2 agonists, such as AL002, DNL919, and VG-3927, enhance microglial survival, plaque compaction, and mitochondrial respiration in AD models, although clinical efficacy may depend on disease stage and metabolic fitness. Exercise training represents a complementary strategy that similarly enhances TREM2 expression, restores microglial homeostasis, and improves mitochondrial metabolism. Both aerobic and resistance exercise activate TREM2-dependent signaling pathways to reduce neuroinflammation and support synaptic integrity. Collectively, these findings highlight TREM2 as a central immunometabolic regulator and suggest that combining TREM2-targeted therapeutics with exercise may offer a synergistic strategy to slow neurodegeneration in AD.