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Background: Genetic factors are increasingly being recognized as important contributors to the pathogenesis of Alzheimer's disease (AD). While the expression of most AD risk genes is enriched in microglia, which leads to microglial dysfunction and amyloid‐beta (Aβ) accumulation, emerging studies suggest that changes in the brain micro‐environment—typically changes in the levels of soluble factors—also modulate microglial functions and disease‐related pathological changes. Therefore, understanding the genetic regulation and pathogenic roles of those soluble factors in AD will help clarify the pathophysiological mechanisms of the disease. Method: We examined the changes in the level of soluble ST2 (sST2), a decoy receptor of IL‐33/ST2 signaling, in the blood and brains of patients with AD, and performed a genome‐wide association study (GWAS) for sST2 to understand its genetic regulations. Result: We showed that elevated sST2 levels are associated with more severe neurodegeneration and Aβ pathological lesions in patients with AD. Our GWAS analysis identified a genetic variant in IL1RL1 (the gene encoding sST2) that is associated with decreased sST2 levels in the blood and brain in AD. Furthermore, we demonstrated that female APOE‐ε4 carriers harboring the genetic variant exhibit decreased sST2 level and reduced risk of AD as well as decreased Aβ accumulation through enhancing microglial activation and colocalization with Aβ. Conclusion: These findings demonstrate how sST2 level in the brain milieu is modulated by a genetic variation and plays a disease‐causing role in AD through microglial clearance of Aβ, and might thus be a novel target for AD therapy. [ABSTRACT FROM AUTHOR]