Causal association between circulating angiopoietin‐1 levels and the risk of Alzheimer’s disease

Background Alzheimer’s disease (AD), characterized by cognitive decline and memory loss, is the most common neurodegenerative disorder. Angiopoietin‐1 is a protein that plays a role in the formation and maintenance of blood vessels and has been suggested to be involved in the development of AD. However, the causal relationship between angiopoietin‐1 and AD is not well understood. Method To investigate the causal relationship between angiopoietin‐1 levels and AD risk, we performed a Mendelian randomization (MR) analysis using instrumental variables (IV) identified from genome‐wide association studies (GWAS) summary statistics on blood angiopoietin‐1 levels (N = 3,301) and AD (N = 63,926). Seven different methods, including inverse variance weighted (IVW), MR‐Egger, weighted median, simple median, maximum likelihood, simple mode, and weighted mode, were applied to calculate the causal estimate. Pleiotropic test and heterogeneity analysis were also assessed to evaluate the stability of the estimates. Result Using the IVW method, genetically determined human blood angiopoietin‐1 levels were causally associated with a decreased risk of AD (odds ratio [OR] = 0.86, 95%CI = 0.78‐0.94, P = 0.001), which was further validated using other approaches (Figure 1A). The leave‐one‐out analysis plot showed that there was no significant outlier driving the overall causal estimate between angiopoietin‐1 levels and AD (Figure 1B). The results of MR‐PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) global, MR‐Egger intercept test, and Cochran’s Q test showed that there were no obvious directional horizontal pleiotropy and heterogeneity, indicating good stability of the present MR study. Conclusion Our study provides evidence for a causal relationship between angiopoietin‐1 levels and a reduced risk of AD. However, further validation and replication of these findings are needed to confirm our results.