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ORIGINAL RESEARCH article
Front. Neurol.
Sec. Dementia and Neurodegenerative Diseases
Volume 16 - 2025 |
doi: 10.3389/fneur.2025.1391182
Causal association of sex hormone-related traits with Alzheimer's Disease: A multivariable and network Mendelian randomization analysis
Provisionally accepted- 1 Zhuzhou Central Hospital, Zhuzhou, Hunan, China
- 2 The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
Background: Although studies have demonstrated a correlation between sex hormone-related traits (such as sex hormone binding globulin (SHBG) and testosterone) and Alzheimer's Disease (AD), the link remains uncertain due to the intricacies of AD pathology. The study aimed to investigate the possible causal link between sex hormone-related traits and AD. Methods: The authors collected data from extensive genome-wide association studies (GWASs) of European ancestry on sex hormone-related traits and AD. Univariate and multivariate Mendelian randomization (MR) analyses were conducted to explore the possible causal relationship between these traits and AD. We used inverse variance weighted (IVW) MR as the main analysis. Results: The use of univariate MR-IVW revealed a possible causal relationship between SHBG [ORs (95% CI), 1.005 (1.001-1.009), p=0.006], testosterone [ORs (95% CI), 0.994 (0.989-0.999), p=0.013] and AD in female. There is no evidence of a causal association of SHBG [ORs (95% CI), 1.002 (0.999-1.005)), p=0.237] and testosterone [ORs (95% CI), 1.000 (0.997-1.004), p=0.810] with AD in males. Multivariate MR analysis revealed a possible direct causal connection between SHBG and testosterone in relation to females AD (SHBG-OR (95%CI), 1.005 (1.001-1.009, p=0.023); testosterone-OR (95%CI), 0.995 (0.989-1.000, p=0.049). Bidirectional MR analysis indicated that SHBG has a possible causal effect on testosterone (SHBG on testosterone-OR (95%CI), 1.064 (1.032-1.096), p=0.0001). The results of the network MR analysis suggested that testosterone may act as a mediator in the causal pathway from SHBG to AD. Conclusion: Our study using the MR methodology indicates that increase of SHBG level and decrease of testosterone level in females are positively linked to an increased risk of developing AD. Importantly, testosterone plays a mediating role in the causal pathway from SHBG to females AD.
Keywords: Alzheimer's disease, Sex hormone-binding globulin (SHBG), Testosterone, neurodegenerative disease, Mendelian randomization
Received: 25 Feb 2024; Accepted: 20 Jan 2025.
Copyright: © 2025 Zhang, Sun, Yang and Fu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Wei-dong Fu, Zhuzhou Central Hospital, Zhuzhou, Hunan, China
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