AbstractIntroduction and aimsGenetic variations play a significant role in determining an individual's AD susceptibility. Research on the connection between AD andTREM1gene polymorphisms (SNPs) remained lacking. We sought to examine the associations betweenTREM1SNPs and AD.MethodsBased on the 1000 Genomes Project data, linkage disequilibrium (LD) analyses were utilized to screen for candidate SNPs in theTREM1gene. AD cases (1081) and healthy control subjects (870) were collected and genotyped, and the associations between candidate SNPs and AD risk were analyzed. We explored the associations between target SNP and AD biomarkers. Moreover, 842 individuals from ADNI were selected to verify these results. Linear mixed models were used to estimate associations between the target SNP and longitudinal cognitive changes.ResultsThe rs2062323 was identified to be associated with AD risk in the Han population, and rs2062323T carriers had a lower AD risk (co‐dominant model: OR, 0.67, 95% CI, 0.51–0.88,p= 0.0037; additive model: OR, 0.82, 95% CI, 0.72–0.94,p= 0.0032). Cerebrospinal fluid (CSF) sTREM2 levels were significantly increased in middle‐aged rs2062323T carriers (additive model: β = 0.18,p= 0.0348). We also found significantly elevated levels of CSF sTREM2 in the ADNI. The rate of cognitive decline slowed down in rs2062323T carriers.ConclusionsThis study is the first to identify significant associations betweenTREM1rs2062323 and AD risk. The rs2062323T may be involved in AD by regulating the expression of TREM1, TREML1, TREM2, and sTREM2. The TREM family is expected to be a potential therapeutic target for AD.