TREM2 and microglial immunity in Alzheimer’s disease: mechanisms, genetics, and therapeutic opportunities
Open accessAbstract
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.
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Enhancing TREM2 signaling may strengthen the ability of microglia to respond to amyloid plaques and neuronal damage.
“TREM2 has attracted therapeutic interest because enhancing TREM2 signaling may strengthen the ability of microglia to respond to amyloid plaques and neuronal damage.”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [53]
Microglial state, not merely plaque burden, is a plausible therapeutic target.
“Newer work continues to examine how TREM2 expression level and activation state influence microglial metabolism and phagocytic capacity, reinforcing the broader principle that microglial state, not merely plaque burden, is a plausible therapeutic target [52,53].”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [53]
TREM2 is a microglial receptor involved in lipid sensing, survival, phagocytosis, metabolism, and plaque-associated microglial responses.
“The best-developed example is TREM2, a microglial receptor involved in lipid sensing, survival, phagocytosis, metabolism, and plaque-associated microglial responses.”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [53]
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Self-citation
- Authors
- Wang, T., Liu, X., Wang, X., Hua, F., & Yan, L.
- Affiliations
- Nanchang University (CN)
- Xinjiang Medical University (CN)
- People's Hospital of Xinjiang Uygur Autonomous Region (CN)
- Corresponding author
- Yan, Lei
- ORCID
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2026-02-18
- Volume
- 17
- Pages
- 1739875-1739875
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC12956735
- OpenAlex
- W7130354338
- Cited by
- 14
- References
- 116
- Citations by year
- 2026: 14
- FWCI
- 10.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Jiangxi Province
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- TREM2, Alzheimer's disease, microglia, neuroinflammation, disease-associated microglia, amyloid plaques, soluble TREM2, phagocytosis, microglial metabolism, tauopathy, disease-modifying therapy
- MeSH terms
- Alzheimer Disease, Animals, Humans, Immunotherapy, Membrane Glycoproteins, Receptors, Immunologic, Microglia
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