REVIEW article
Front. Immunol.
Sec. Multiple Sclerosis and Neuroimmunology
This article is part of the Research TopicImmune Responses in Neurodegeneration: Opportunities for Targeted InterventionsView all 9 articles
TREM2 and Microglial Immunity in Alzheimer's Disease: Mechanisms, Genetics, and Therapeutic Opportunities
Provisionally accepted
- 1Nanchang University Jiangxi Medical College, Nanchang, China
- 2People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- 3Nanchang University Second Affiliated Hospital, Nanchang, China
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Alzheimer's disease (AD) is increasingly recognized as a disorder of innate immune dysregulation within the central nervous system. The triggering receptor expressed on myeloid cells 2 (TREM2), a microglial immunoreceptor, has emerged as a pivotal genetic risk factor for late-onset AD, underscoring the critical role of neuroimmune interactions in disease pathogenesis. This review synthesizes recent advances concerning TREM2's modulation of core microglial functions, including phagocytosis, inflammatory signaling, cellular metabolism, and survival, processes that are essential for responding to amyloid-β plaques and neuronal damage. We highlight the TREM2-APOE pathway as a central mechanism driving the disease-associated microglia (DAM) phenotype and examine how loss-of-function mutations such as R47H disrupt immune surveillance, aggravate amyloid pathology, and promote neuroinflammation. Additionally, we explore the diagnostic and therapeutic potential of soluble TREM2 (sTREM2) and TREM2-targeted immunotherapies, which enhance plaque encapsulation and cognitive outcomes in preclinical models. By integrating genetic, molecular, and clinical evidence, this review establishes TREM2 as a keystone regulator linking amyloidosis, tauopathy, and neuroinflammation, highlighting its promise as a target for disease-modifying therapies.
Keywords: Alzheimer's disease, Immunotherapy, Microglia, neuroimmunology, TREM2
Received: 05 Nov 2025; Accepted: 04 Feb 2026.
Copyright: © 2026 Wang, Liu, Wang, Hua and Yan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Lei Yan
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