The Causal Relationship Between Blood Zinc, Serum Transferrin and Alzheimer’s Disease in Europeans: A Two-Sample Bidirectional Mendelian Randomization Study

Background: Metal elements have been reported to be associated with Alzheimer’s disease (AD). The available epidemiological evidence for these associations is often inconsistent and prone to confounding and reverse causation. We aimed to explore the causal effects of varying metal element levels on AD and investigate potential underlying mechanisms. Methods: To investigate the causal link between multiple metals and AD risk, we employed a bidirectional two-sample Mendelian randomization (TSMR) approach and used single nucleotide polymorphisms (SNPs) as instrumental variables. And the participants were extracted from large GWAS databases in the European Cohort. Our analysis primarily utilized methods including inverse variance weighted (IVW), weighted median, and MR-Egger, and used sensitivity analyses to assess pleiotropy and heterogeneity. To verify the mechanism, we further used the metal element-related genes and disease-related genes to construct a protein–protein interaction (PPI) network. Results: The IVW method results from Mendelian randomization (MR) analysis showed that blood zinc was negatively associated with AD risk (OR = 0.96, 95%CI: 0.93–0.99, p = 0.016) in the forward MR analysis, whereas AD was negatively associated with serum transferrin levels (OR = 0.89, 95%CI: 0.81–0.98, p = 0.015) in the reverse MR analysis in Europeans, which was adjusted for BMI, smoking, education, and coffee intake. However, no causal links were found between blood Cu, Mg, Se, and other iron states in serum and AD risk in Europeans. The PPI network suggested that SLC39A1 played a key role in the zinc–AD relationship, and transferrin might interact with ALB, LTF, HFE, TFRC, TF, and SLC40A1 in the context of AD. Conclusions: Our TSMR study suggested that in European populations, higher blood zinc levels might exert a protective effect against AD, whereas pathology of might lead to decreased serum transferrin levels. These findings provided evidence for metal dysregulation in AD, though further validation through randomized controlled trials is required.