An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer's disease

Changes 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)-epsilon 4 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 (A beta) pathology through the modulation of microglial activation and A beta clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.

Automated summary

Changes in circulating protein levels are associated with AD, but their specific roles in AD are still unclear. In this study, the researchers identified a new disease-causing factor, soluble ST2 (sST2), and a genetic variant, rs1921622, that downregulates sST2 levels. They found that increased sST2 levels are associated with more severe pathological changes in female individuals with AD, and decreased sST2 levels lower AD risk and related endophenotypes, especially in Chinese populations. Transcriptome and immunohistochemical studies revealed that sST2 regulates Aβ pathology through microglial activation and Aβ clearance.