Relationship Between Sphingomyelin and Risk of Alzheimer’s Disease: A Bidirectional Mendelian Randomization Study

Abstract

Background: Alzheimer’s disease (AD) is a complex neurodegenerative disorder whose etiology involves multiple genetic and environmental factors. Sphingomyelin (SM) is a type of sphingolipid found in cell membranes, and recent evidence suggests a potential link between SM and AD. However, the nature of this relationship remains unclear. Objective: To elucidate the potential causal relationship between SM levels and the risk of developing AD using a two-sample Mendelian randomization approach. Methods: The study utilized data extracted from the genome wide association study database. The primary analysis method was the inverse variance weighted (IVW) method, which was supplemented by weighted median, weighted mode, and MR Egger methods. The study specifically investigated the bidirectional causal relationship between SM and AD, evaluating odds ratios (OR) with a 95% confidence interval (95% CI). Results: Elevated levels of SM were found to be a risk factor for AD, as shown by IVW(MRE) [OR: 1.001, 95% CI: 1.000 to 1.002; p = 0.020 < 0.05], IVW(FE) [OR: 1.001, 95% CI: 1.001 to 1.002; p = 3.36e-07 < 0.05], and MR Egger. Conversely, AD was demonstrated to lead to an increase in SM levels [IVW(MRE): OR: 5.64e+08, 95% CI: 1.69e+05 to 1.89e+12; p = 1.14e-06 < 0.05], with consistent findings across the IVW(FE), MR Egger, weighted median, and weighted mode methods. Conclusions: The study establishes a bidirectional positive correlation between SM and AD. Increased SM levels are associated with a higher risk of developing AD, and the presence of AD can further elevate SM levels, potentially exacerbating the disease’s progression.