Causal effect of serum lipopolysaccharide activity levels and inflammatory proteins on Alzheimer's disease: A Mendelian randomization study combined with meta-analysis in a large-scale cohort.

Background: Neuroinflammation represents a central pathological mechanism in Alzheimer's disease (AD). Lipopolysaccharide (LPS) is a potent inducer of neuroinflammation and demonstrates elevated circulating levels in AD patients. Objective: This study aims to investigate the genetic association between serum LPS activity level, inflammatory proteins and AD. Methods: A two-sample mendelian randomization (MR) analysis was performed to explore the causal effect of serum LPS activity level and 91 inflammatory proteins on AD, including 1, 260, 136 sporadic AD and 2, 838, 825 familial AD patients, respectively. Meta-analysis was conducted on multiple datasets to determine statistically significant results that was initially observed in one dataset. Results: Serum LPS activity level is a risk factor for early onset sporadic AD with OR = 1.392, 95% CI: 1.038-1.869. In most other sporadic AD datasets, LPS shows a trend of increasing the risk of AD onset. After meta-analysis in 10 independent datasets, no association between LPS and sporadic AD was observed. In most familial AD datasets, LPS level demonstrated a trend of decreasing AD risk in MR analysis, however, meta-analysis of the combined 8 datasets showed no statistically significant difference. Two inflammatory proteins, AXIN1 and IL-1 alpha, were identified as significant risk factors for sporadic AD. Conclusions: This study suggested that serum LPS activity level may present a risk effect in early onset sporadic AD. Two inflammatory proteins AXIN1 and IL-1 alpha were associated with the risk of sporadic AD. These findings provide a new perspective for the early diagnosis and treatment of sporadic and familial AD.