Alzheimer’s disease (AD) is the most common form of dementia. Rare variants in triggering receptor expressed on myeloid cells 2 (TREM2) have been identified as risk factors for AD. Soluble TREM2 (sTREM2) in the cerebrospinal fluid (CSF) is a potential and novel biomarker of neuroinflammation implicated in the onset and progression of AD. To explore the roles of CSF sTREM2 on the pathogenesis of AD, we performed genome-wide association studies (GWAS) by using the data from Alzheimer’s Disease Neuroimaging Initiative (ADNI). We found CSF sTREM2 levels were elevated with the disease stages, but there was no significant difference between that of AD patients and normal participants. CSF sTREM2 was positively correlated with CSF total tau and phosphorylated-tau levels (ρ > 0.35, p < 1e-06; ρ > 0.32, p < 1e-05, respectively) for all disease states. We identified the most significant CSF sTREM2 related locus was rs7232 (FDR = 3.01e-08), a missense variant in MS4A6A gene of chromosome 11. Moreover, we also detected rs7232 was highly associated with MS4A6A gene expression (FDR = 1.37e-18). In addition, our pathway analysis for our significant GWAS results showed that biological processes for regulation of viruses and immune response were highly overrepresented or enriched. Our study suggests that CSF sTREM2 plays an informative role in AD progression. Moreover, CSF sTREM2 and AD is highly related to viral infections and immune response.