TREM2-directed therapy in Alzheimer’s disease: from therapeutic window to clinical translation

Abstract

Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) deposition, tau pathology, synaptic dysfunction, and a sustained neuroimmune response. Among immune-related targets, triggering receptor expressed on myeloid cells 2 (TREM2) is of particular interest because it is supported by human genetics, microglial biology, and expanding therapeutic development. TREM2 regulates microglial survival, phagocytosis, lipid handling, metabolic fitness, and plaque-associated responses, yet its therapeutic significance is more complex than a simple protective receptor model suggests. Although multiple TREM2-directed strategies have entered preclinical and early clinical development, recent evidence indicates that pharmacological target engagement does not necessarily translate into clinical benefit. We therefore propose that the therapeutic value of TREM2 is best understood through the concept of therapeutic window. TREM2 modulation is more likely to be beneficial when amyloid pathology is still being actively contained and microglial functional reserve remains preserved, whereas later disease stages, tau-associated neurodegeneration, receptor shedding, genetic heterogeneity, and pre-existing immune dysfunction may narrow or alter treatment benefit. Within this framework, soluble TREM2 (sTREM2) should be interpreted cautiously, as it may reflect receptor shedding, target engagement, microglial state, disease stage, or a combination of these processes rather than serving as a direct surrogate of efficacy. Viewed in this way, the central challenge of TREM2-directed therapy is to determine both when receptor modulation can still produce meaningful tissue protection and how the mode of receptor engagement shapes adaptive or maladaptive microglial programs.