Jiang, YuanbingZhou, XiaopuWong, Hiu YiOuyang, LiIp, Fanny C. F.Chau, Vicky M. N.Lau, Shun-FatWu, WeiWong, Daniel Y. K.Seo, HeukjinFu, Wing-YuLai, Nicole C. H.Chen, YuewenChen, YuTong, Estella P. S.Alzheimer’s Disease Neuroimaging InitiativeMok, Vincent C. T.Kwok, Timothy C. Y.Mok, Kin Y.Shoai, MaryamLehallier, BenoitMorán Losada, PatriciaO'Brien, EleanorPorter, TenielleLaws, Simon M.Hardy, JohnWyss-Coray, TonyMasters, Colin L.Fu, Amy K. Y.Ip, Nancy Y.2025-03-052025-03-052022Jiang Y, Zhou X, Wong HY, et al. An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer's disease. Nat Aging. 2022;2(7):616-634. doi:10.1038/s43587-022-00241-9https://hdl.handle.net/1805/46223Changes in the levels of circulating proteins are associated with Alzheimer's disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33-ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR-Cas9 genome editing identified rs1921622 , a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622 , demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622 /sST2 regulates amyloid-beta (Aβ) pathology through the modulation of microglial activation and Aβ clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.en-USAttribution 4.0 InternationalAlzheimer's diseaseNeuroimmunologyGenetics of the nervous systemAgeingArticle