Causality relationship between 91 inflammatory factors and Alzheimer disease: A bidirectional Mendelian randomization study

Alzheimer disease (AD) is a neurodegenerative disorder characterized by amyloid plaque deposition, neurofibrillary tangles, and chronic neuroinflammation. Due to its complexity and difficult-to-treat nature, it has cast a huge shadow over global health. In addition to genetic susceptibility, the development of AD is closely related to systemic inflammation. This study aims to evaluate the association between systemic inflammatory factors and AD through a bidirectional Mendelian randomization (MR) design. Our MR design incorporated aggregated data from extensive genome-wide association studies to investigate the causal relationship between genetically determined systemic inflammatory factors and AD. The MR analysis results identified 9 potential systemic inflammatory regulatory factors: C-X-C motif chemokine 5, interleukin-18 receptor 1, interleukin-6, and tumor necrosis factor, which were associated with an increased risk. Conversely, AD is significantly correlated with 5 circulating inflammatory regulatory factors, namely, tumor necrosis factor-related apoptosis-inducing ligand, stem cell factor, monocyte chemoattractant protein-4, interleukin-5, and cystatin D, which are considered downstream consequences of AD. It is worth noting that our results have, for the first time, clarified the significant roles of inflammatory factors such as cystatin D and monocyte chemoattractant protein-4 in AD, providing new markers and key targets for further exploration of the molecular mechanism and clinical diagnosis and treatment of AD.