The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk

Common variants in the microglia-specific MS4A gene cluster modify risk for late-onset Alzheimer’s disease and modulate extracellular soluble TREM2. TREM2 takes center stage Genetic variants in triggering receptor expressed on myeloid cells 2 (TREM2) are associated with Alzheimer’s disease (AD) risk. Soluble TREM2 (sTREM2) concentrations in cerebrospinal fluid (CSF) change with AD progression; however, genetic modifiers of CSF sTREM2 remain unknown. Deming and colleagues now report two independent genetic associations in the membrane-spanning 4-domains subfamily A (MS4A) gene region. An AD risk variant was associated with reduced CSF sTREM2 concentrations, whereas a different variant leading to reduced AD risk was associated with elevated CSF sTREM2 concentrations. Gene expression analyses and molecular studies of human macrophages validated a functional relationship between MS4A4A and sTREM2 concentrations. Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer’s disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer’s Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 × 10−15); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.