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Causal effects of genetically predicted testosterone on Alzheimer’s disease: a two-sample mendelian randomization study

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Abstract

Objective

Although several studies have reported that testosterone may protect against Alzheimer’s disease, no evidence of a causal relationship has been demonstrated.

Methods

A Mendelian randomization (MR) study was performed to determine the causal role of testosterone in Alzheimer’s disease. The study utilized public databases obtained from separately published genome-wide associationstudies (GWAS). Single-nucleotide polymorphisms (SNPs) for testosterone were extracted from the most recent and largest published GWAS meta-analysis (178,782 participants), and SNPs for Alzheimer’s disease were extracted from UK Biobank (954 AD cases and 487,331 controls). The odds ratio (OR) of the inverse variance weighting (IVW) approach was the primary outcome, and the weighted median and MR Egger regression were used for sensitivity analysis.

Results

Through IVW, we observed a causal association between genetically predicted testosterone and the risk of Alzheimer’s disease, with an OR of 0.99 (95% confidence interval [CI] = 0.998–0.999, p = 0.047). In the sensitivity analyses, the weighted median regression showed directionally similar estimates (OR = 0.99, 95% CI = 0.998–0.999, p = 0.048). The MR Egger regression showed similar estimates (OR = 0.99, 95% CI = 0.998–1.00, p = 0.35), but with lower precision. Funnel plots, MR Egger intercepts, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) analysis indicated the absence of directional pleiotropy effects.

Conclusion

In conclusion, our MR study provides evidence of a causal relationship between testosterone levels and Alzheimer’s disease; however, this relationship must be validated in future studies with larger sample sizes. Early testosterone monitoring may enable the prevention of Alzheimer’s and related diseases.

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Data availability

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

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Acknowledgements

We appreciate the linguistic assistance provided by TopEdit (www.topeditsci.com) during the preparation of this manuscript.The authors would like to thank all the genetics consortiums for making the GWAS summary data publicly available.

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There was no funding for this research.

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Authors and Affiliations

  1. Department of Neurology, Suzhou Wujiang District Hospital of Traditional Chinese Medicine (Suzhou Wujiang District Second People’s Hospital), Wujiang District, Suzhou, 215200, China

    Qian Xu, Hong Shen, Yifan Zhu, Junlei Zhang, Zhongmei Shen, Jianming Jiang & Jie Zhou

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Contributions

XQ and ZJ designed the study. XQ, ZY, and SH conducted research. XQ and Zhang J analyzed the data. XQ, SZ, JJ, and SH wrote this paper. All authors contributed to the article and approved the submitted version.

Corresponding author

Correspondence to Jie Zhou.

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Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

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Xu, Q., Shen, H., Zhu, Y. et al. Causal effects of genetically predicted testosterone on Alzheimer’s disease: a two-sample mendelian randomization study. Acta Neurol Belg 124, 591–601 (2024). https://doi.org/10.1007/s13760-023-02426-4

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