Genetically proxied IL‐6 signaling and risk of Alzheimer's disease and lobar intracerebral hemorrhage: A drug target Mendelian randomization study

Abstract

Abstract 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.

Keywords

• Alzheimer's disease
• amyloid
• C‐reactive protein
• IL‐6
• intracerebral hemorrhage
• Mendelian randomization