Work

Causal association of sex hormone-related traits with Alzheimer’s disease: a multivariable and network Mendelian randomization analysis

Year: 2025

Type: article

Abstract: 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.

Source: Frontiers in Neurology

DOI: 10.3389/fneur.2025.1391182

Authors: Yan Zhang, Zhen-dong Sun, Yu-shen Yang, Wei-dong Fu

Institutions: Central South University, Fujian Medical University, Second Affiliated Hospital of Fujian Medical University

Language: English

Topic: Dementia and Cognitive Impairment Research

Subfield: Psychiatry and Mental health

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801