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The common p. D358A variant (rs2228145) in IL-6R is associated with risk for multiple diseases and with increased levels of soluble IL-6R in the periphery and central nervous system (CNS). Here, we show that the p. D358A allele leads to increased proteolysis of membrane bound IL-6R and demonstrate that IL-6R peptides with A358 are more susceptible to cleavage by ADAM10 and ADAM17. IL-6 responsive genes were identified in primary astrocytes and microglia and an IL-6 gene signature was increased in the CNS of late onset Alzheimer’s disease subjects in an IL6R allele dependent manner. We conducted a screen to identify variants associated with the age of onset of Alzheimer’s disease in APOE 4 carriers. Across five datasets, p. D358A had a meta P= 3× 10− 4 and an odds ratio= 1.3, 95% confidence interval 1.12–1.48. Our study suggests that a common coding region variant of the IL-6 receptor results …