Human Trace Elements, Gut Microbiota, and Alzheimer's Disease: Insights From Multistage Mendelian Randomization Analysis

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline that ultimately impairs independent living. Previous studies have identified associations between certain trace elements or gut microbiota and AD, but few have explored the interplay among all three. This study aimed to elucidate the relationship between 17 human trace elements and AD using Mendelian randomization (MR) and multivariate MR (MVMR) analysis. In addition, the potential mediating role of 412 gut microbiota in the relationship between trace elements and AD was investigated using mediation MR analysis. MR analysis revealed the genetic causal associations of copper (Odds Ratio [OR] = 1.291, 95% Confidence Interval [CI]: 1.075-1.551) and carotene (OR = 2.805, 95% CI: 1.054-7.466) with AD. MVMR analysis further supported that copper (OR = 1.262, 95% CI: 1.084-1.468) and carotene (OR = 4.550, 95% CI: 1.245-16.631) were independent risk factors for AD. Mediation MR analysis indicated that increased copper levels enhance lipid biosynthesis pathways (OR = 1.125, 95% CI: 1.046-1.210), contributing to a higher AD risk (OR = 1.822, 95% CI: 1.036-3.206), with a mediation effect of 27.636%. Elevated carotene levels were associated with reduced pentose phosphate pathway activity and decreased abundance of f_Prevotellaceae.g_Paraprevotella, both of which were linked to increased AD risk, with mediation effects of 25.527% and 32.140%, respectively. This study highlights copper and carotene as potential targets for novel AD interventions and underscores the complex interplay between trace elements, gut microbiota, and neurodegenerative diseases.