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INTRODUCTION: Evidence suggests that higher C-reactive protein (CRP) is associated with lower risk of Alzheimer's disease (AD) and lobar intracerebral hemorrhage (ICH). Whether interleukin (IL)-6 signaling, an active pharmacological target upstream of CRP, is associated with these amyloid-related pathologies remains unknown.METHODS: We used 26 CRP-lowering variants near the IL-6 receptor gene to perform Mendelian randomization analyses for AD (111,326 cases, 677,663 controls) and ICH (1545 cases, 1481 controls). We explored the effect of genetically proxied IL-6 signaling on serum, cerebrospinal fluid (CSF), and brain proteome (971 individuals).RESULTS: Genetically upregulated IL-6 receptor-mediated signaling was associated with lower risk of AD (OR per increment in serum logCRP levels: 0.87, 95% CI: 0.79-0.95) and lobar ICH (OR: 0.27, 95% CI: 0.09-0.89). We also found associations with 312, 77, and 79 brain, CSF, and plasma proteins, respectively, some of which were previously implicated in amyloid-clearing mechanisms.DISCUSSION: Genetic data support that CRP-lowering through variation in the gene encoding IL-6 receptor may be associated with amyloid-related outcomes.HIGHLIGHTS: Genetic variants proxying IL-6 inhibition are associated with AD and lobar ICH risk.The variants are also associated with amyloid clearing-related proteomic changes.Whether pharmacologic IL-6 inhibition is linked to AD or lobar ICH merits further study.