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

Myserlis, Evangelos Pavlos ; Ray, Anushree; Anderson, Christopher D.; Georgakis, Marios K. (2024): Genetically proxied IL‐6 signaling and risk of Alzheimer's disease and lobar intracerebral hemorrhage: A drug target Mendelian randomization study. Alzheimer's & Dementia: Translational Research & Clinical Interventions, 10 (3): e70000. ISSN 2352-8737

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.

• Dokumententyp: Artikel (Klinikum der LMU)
• Organisationseinheit (Fakultäten): 07 Medizin > Munich Cluster for Systems Neurology (SyNergy); 07 Medizin > Klinikum der LMU München > Institut für Schlaganfall- und Demenzforschung (ISD)
• DFG-Fachsystematik der Wissenschaftsbereiche: Lebenswissenschaften
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198