TREM2 Signaling and Alzheimer's Disease: Experimental Modulators, Progress, and Challenges

Alzheimer's Disease (AD) is the leading cause of dementia worldwide, with a growing global burden and limited disease-modifying therapeutic options. The transmembrane receptor termed triggering receptor expressed on myeloid cells 2 (TREM2), which is mainly expressed by myeloid cells, has emerged as a target of interest in AD due to its role in modulating microglia functions, including cholesterol metabolism, phagocytosis of amyloid-beta (Aβ), inflammatory signaling, and innate immune neuronal protection. Genetic research has also shown that partial loss-of-function mutations in the TREM2 gene, particularly the R47H and R62H variants, substantially increase the risk of late-onset AD, further underscoring the therapeutic rationale for enhancing TREM2 signaling to combat the disease. Therapeutic strategies targeting TREM2 have exponentially increased in recent years, spanning monoclonal antibodies (mAbs) with distinct epitopes and mechanisms of receptor modulation, orally bioavailable small-molecule drugs capable of penetrating the blood-brain barrier (BBB), and upstream mechanisms targeting the shedding of the TREM2 ectodomain. Early clinical trials have revealed that target engagement does not translate directly into clinical benefit in patients, highlighting knowledge gaps in the timing of intervention, patient selection, dose optimization, and the complex dichotomy of TREM2 signaling, in which both insufficient and excessive activation may be detrimental to AD patients. Nonetheless, the continued advancement of therapeutics into clinical trials reflects the confidence in the underlying scientific rationale. This narrative review summarizes the current understanding of wild-type and variant TREM2 signaling in AD pathogenesis, evaluates the preclinical and clinical evidence supporting each class of TREM2-targeted therapeutic strategies, and discusses the challenges, emerging insights, and future directions that could shape the next generation of TREM2-based interventions for AD.