Alzheimer's disease (AD), the most common cause of dementia, is characterized by amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). The pathogenesis is complex and involves multiple factors, including age, environment, and genetics. Genetic predisposition plays a significant role, with heritability estimated at 60-80%. The apolipoprotein E (ApoE) gene is a major genetic risk factor; the ε4 allele significantly increases LOAD risk, while the ε2 allele decreases it. ApoE isoforms affect Aβ clearance, aggregation, and metabolism, and also modulate tau-mediated neurodegeneration. Genome-wide association studies (GWAS) have identified several novel genetic risk factors for LOAD, many related to microglial function and inflammation, such as TREM2. TREM2 variants increase LOAD risk by 2-4 fold, comparable to one copy of APOE ε4. This review examines the role of TREM2 in LOAD, focusing on its structure, expression, signaling, and functions, as well as its potential as a therapeutic target.

The literature review extensively covers existing knowledge on TREM2 and its role in various neurological diseases. It begins with the structure and expression of TREM2 across different myeloid cells including the brain's microglia, noting variations in expression across brain regions and modulation by inflammatory factors. The review explores TREM2 signaling, primarily mediated by the adaptor protein DAP12, and the uncertain identities of its ligands. Existing studies suggest TREM2 binds microbial products, lipids, and apolipoproteins, including ApoE and clusterin. The functional aspects of TREM2 are well-established; it enhances phagocytosis, modulates inflammatory signaling (mostly showing anti-inflammatory effects, although some studies suggest pro-inflammatory roles), and influences myeloid cell number, proliferation, and survival. The review also discusses the link between TREM2 variants and AD, emphasizing the R47H variant's impact on ligand binding, signaling, and phagocytic functions. Finally, the interplay between TREM2 and ApoE in AD pathogenesis is reviewed.

This review article uses a systematic review methodology. The authors searched relevant databases for published studies on TREM2 and its role in Alzheimer's disease, focusing on the past five years of research. The search terms included "TREM2," "Alzheimer's disease," "microglia," "amyloid beta," "tau," "ApoE," and related keywords. The inclusion criteria were studies published in peer-reviewed journals focusing on the roles of TREM2 in Alzheimer's disease pathogenesis and its potential therapeutic implications. Studies were selected based on their relevance to the topic, methodology rigor, and impact on the field. Data extraction involved carefully reviewing and summarizing key findings from each selected study. The authors critically evaluated the studies for methodological limitations and potential biases, including study designs, sample sizes, and the use of different animal models. This information was synthesized to provide a comprehensive understanding of the current knowledge regarding TREM2's role in Alzheimer's disease.

Several key findings are presented: 1) TREM2's expression is primarily in microglia, varies across brain regions, and is modulated by inflammation. 2) TREM2 signaling, via DAP12, activates downstream pathways influencing microglial function. 3) TREM2 enhances phagocytosis and modulates inflammation (mostly anti-inflammatory). 4) AD-associated TREM2 variants (e.g., R47H) impair TREM2 function, affecting ligand binding, signaling, and phagocytosis. 5) In vivo studies on amyloid pathology show inconsistent effects of TREM2 deficiency on Aβ accumulation, possibly due to age or Aβ burden dependence. However, TREM2 deficiency consistently decreases microglial activation and plaque-associated microglia, leading to defective plaque compaction and increased dystrophic neurites. 6) Studies on the link between TREM2 and tau pathology suggest a biphasic effect of TREM2 loss-of-function, potentially promoting tau pathology in early stages but protecting against neurodegeneration in later stages. 7) There's strong evidence for collaboration between TREM2 and ApoE in AD pathogenesis, potentially driving the switch from homeostatic to neurodegenerative microglia. 8) TREM2 is a potential therapeutic target for AD, but the optimal strategy (activation or inhibition) and timing remain uncertain. The review highlights the complexity of TREM2's role in AD, with both beneficial and detrimental effects depending on disease stage and context.

This review highlights the complex and multifaceted role of TREM2 in Alzheimer's disease. While initially identified as a risk factor based on genetic association studies, the functional consequences of TREM2 variants and the interplay with other key molecules like ApoE have unveiled a nuanced picture. The findings suggest that TREM2 may play a dual role, both contributing to the progression of the disease in early stages and potentially offering protective effects in later stages. The inconsistencies observed in in vivo studies on the effects of TREM2 deficiency on amyloid burden necessitate further research to clarify the timing and nature of its impact. The collaboration between TREM2 and ApoE suggests a significant pathway in microglial dysfunction and neurodegeneration, a concept reinforced by the identification of a neurodegeneration-associated microglial phenotype (MGnD). This adds complexity to the prospects of therapeutic targeting, underscoring the need for a well-defined strategy that considers both the timing and the mode of intervention to avoid exacerbating the disease process. The successful development of TREM2-targeted therapies requires a better understanding of the intricate interplay between TREM2, ApoE, amyloid pathology, and tau pathology.

The review comprehensively analyzes the current understanding of TREM2's role in Alzheimer's disease, highlighting its importance in both amyloid and tau pathologies and its interaction with ApoE. It emphasizes the complexity of TREM2's function, varying across disease stages and contexts. While therapeutic targeting of TREM2 holds promise, further research is crucial to clarify its dual role and determine the optimal therapeutic strategy. Future studies should focus on in vivo studies using models of both amyloid and tau pathologies, focusing on partial loss-of-function TREM2 models mirroring the human genetic variants. Understanding the precise interplay between TREM2, ApoE, and Aβ will be key to developing effective TREM2-based therapies.

This review primarily focuses on findings from mouse models and in vitro studies. The direct translatability of these findings to human AD remains a limitation. Inconsistent results across different in vivo studies highlight the complexity of studying TREM2 function in AD and the need for larger, more controlled studies involving diverse human populations. The review also acknowledges the lack of sufficient data on the precise mechanisms by which TREM2 variants alter AD pathogenesis.