Analysis of the causal relationship between five chosen factors and early-onset Alzheimer's disease: A Mendelian randomization study

Background This study aims to explore the causal relationship between five selected factors— lysosome, migrasomes, macrophage, fibroblast, and endothelium cell—and early-onset Alzheimer's disease (EOAD) through related genes, providing clues for EOAD research. Methods Using genes related to the five selected factors as exposure variables and EOAD as the disease outcome, significant genes were screened through Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW) method, based on the OpenGWAS database. The selected genes were intersected with genes related to the exposure factors to assess the causal relationships between the five factors and EOAD. Results MR analysis identified 13 genes in total. Six of these genes were protective factors for EOAD, with LYST being the most significant (OR = 0.4259, 95% CI: 0.2218–0.8178, p = 0.0103). Seven genes were risk factors for EOAD, with NCF4 being the most significant (OR = 2.7207, 95% CI: 1.0229–7.2362, p = 0.0449). A total of 1925 genes related to lysosome, migrasomes, macrophage, fibroblast, and endothelium cell were analyzed. After intersection, 10 lysosome-related genes (NCF4, VIPAS39, LYST, SORT1, ARSB, EPDR1, SYNGR1, ANXA11, PYGB, CLN5) and 3 endothelium cell -related genes (ADM, NFIB, NKTR) were found to have significant causal relationships with EOAD. Conclusions There are genes related to lysosome and endothelium cell that have significant relationships with EOAD, while no causal relationships were found between migrasomes, macrophage, fibroblast, and EOAD. This study provides an important basis for further EOAD research.