TREM2-agonist antibodies as an emerging therapeutic strategy for Alzheimer's disease: a systematic review of in vivo preclinical evidence

Background: Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Its pathogenesis involves persistent glial-mediated neuroinflammation. TREM2 regulates microglial function and has emerged as a promising therapeutic target. This systematic review evaluated the evidence on TREM2-agonistic antibodies in experimental AD models. Methods: The protocol was registered in PROSPERO (CRD420261472054). We searched PubMed/MEDLINE, Web of Science, Embase, and Scopus through August 6, 2026, and included original in vivo preclinical studies evaluating TREM2-agonist antibodies in AD models. Results: Fourteen studies were included. Most of them used genetically modified mouse models. Interventions varied in molecular format, valency, epitope, treatment schedule, and brain-delivery strategy. Higher valency enhanced receptor activation. Brain-delivery modules increased central nervous system exposure and microglial responses. Overall, TREM2 agonism promoted microglial phenotypic and functional remodeling, with enhanced plaque-associated recruitment and phagocytic/lysosomal activity. However, responses varied with genetic background, pathological burden, and baseline TREM2 expression. Several studies reported reductions in soluble Aβ, plaque area, filamentous plaques, or total amyloid burden. Tau-related effects were heterogeneous, ranging from reduced phosphorylation and seeding to no effect or worsening of tau pathology. Cognitive/behavioral improvements and neuronal or synaptic preservation were observed across studies. Conclusion: TREM2-agonist antibodies can remodel microglial responses and modify AD-related pathology in preclinical models. However, therapeutic efficacy may vary with the experimental and disease context. Further development will require refinement of antibody design, appropriate selection of therapeutic windows, and identification of patient subgroups most likely to respond.