Causal association of sex hormone-related traits with Alzheimer’s disease: a multivariable and network Mendelian randomization analysis
BackgroundAlthough 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 ca...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2025.1391182/full |
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| author | Yan Zhang Zhen-dong Sun Yu-shen Yang Wei-dong Fu |
| author_facet | Yan Zhang Zhen-dong Sun Yu-shen Yang Wei-dong Fu |
| author_sort | Yan Zhang |
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| description | BackgroundAlthough 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.MethodsThe 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.ResultsThe 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.ConclusionOur 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. |
| format | Article |
| id | doaj-art-cc3d8149062d4f539778a5508aacd066 |
| institution | Kabale University |
| issn | 1664-2295 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Neurology |
| spelling | doaj-art-cc3d8149062d4f539778a5508aacd0662025-02-05T05:17:47ZengFrontiers Media S.A.Frontiers in Neurology1664-22952025-02-011610.3389/fneur.2025.13911821391182Causal association of sex hormone-related traits with Alzheimer’s disease: a multivariable and network Mendelian randomization analysisYan Zhang0Zhen-dong Sun1Yu-shen Yang2Wei-dong Fu3Department of Anesthesiology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan, ChinaDepartment of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, ChinaDepartment of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, ChinaDepartment of Anesthesiology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan, ChinaBackgroundAlthough 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.MethodsThe 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.ResultsThe 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.ConclusionOur 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.https://www.frontiersin.org/articles/10.3389/fneur.2025.1391182/fullAlzheimer’s diseasesex hormone-binding globulin (SHBG)testosteroneneurodegenerative diseaseMendelian randomization |
| spellingShingle | Yan Zhang Zhen-dong Sun Yu-shen Yang Wei-dong Fu Causal association of sex hormone-related traits with Alzheimer’s disease: a multivariable and network Mendelian randomization analysis Frontiers in Neurology Alzheimer’s disease sex hormone-binding globulin (SHBG) testosterone neurodegenerative disease Mendelian randomization |
| title | Causal association of sex hormone-related traits with Alzheimer’s disease: a multivariable and network Mendelian randomization analysis |
| title_full | Causal association of sex hormone-related traits with Alzheimer’s disease: a multivariable and network Mendelian randomization analysis |
| title_fullStr | Causal association of sex hormone-related traits with Alzheimer’s disease: a multivariable and network Mendelian randomization analysis |
| title_full_unstemmed | Causal association of sex hormone-related traits with Alzheimer’s disease: a multivariable and network Mendelian randomization analysis |
| title_short | Causal association of sex hormone-related traits with Alzheimer’s disease: a multivariable and network Mendelian randomization analysis |
| title_sort | causal association of sex hormone related traits with alzheimer s disease a multivariable and network mendelian randomization analysis |
| topic | Alzheimer’s disease sex hormone-binding globulin (SHBG) testosterone neurodegenerative disease Mendelian randomization |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2025.1391182/full |
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