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The influence of growth and sex hormones on risk of alzheimer’s disease: a mendelian randomization study

  • NEURO-EPIDEMIOLOGY
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Abstract

Alzheimer’s disease is more prevalent in women, possibly due to sex or growth hormones but existing evidence is inconclusive. We investigated whether genetically predicted sex and growth hormones are associated with risk of Alzheimer’s disease. Genetic variants strongly and independently predicting insulin-like growth factor 1 (IGF-1), testosterone and sex hormone-binding globulin (SHBG) were obtained from large, published genome wide associations studies (GWAS) and applied to GWAS of Alzheimer’s disease based on clinical diagnosis (cases = 21,982, control = 41,944) from the International Genomics of Alzheimer’s Project and the UK Biobank parental (maternal cases = 27,696; paternal cases = 14,338) and siblings’ diagnosis (cases = 2,171) as proxy cases. Published GWAS summary statistics were used in our analyses. Estimates were obtained from inverse variance weighting with sensitivity analysis (i.e., MR-Egger, weighted median and MR-PRESSO). Multivariable analyses adjusted for pleiotropic effects and possible sources of selection bias were also performed. Genetically predicted higher total testosterone may reduce the risk of paternal Alzheimer’s disease (odds ratio (OR) 0.86, 95% confidence interval (CI) 0.76 to 0.97, per SD increase in testosterone) and in meta-analysis for women (OR 0.92, 95% CI 0.87, 0.98) with directionally similar results from other analyses. SHBG were not associated with Alzheimer’s disease. IGF-1 in women was inversely associated with risk of clinical Alzheimer’s disease in sensitivity analysis but not in the main analysis. These results suggest genetically predicted higher total testosterone may lower risk of Alzheimer’s disease. The role of testosterone and the immune system in Alzheimer’s disease could be further investigated.

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All data used are publicly available and can be found in the references and supplementary file.

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Acknowledgements

The authors would like to thank Neale Lab (http://www.nealelab.is/uk-biobank/) for conducting the GWAS and providing the sex-specific genetic associations in the UK Biobank. We thank the International Genomics of Alzheimer’s Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i–Select chips was funded by the French National Foundation on Alzheimer’s disease and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2 and the Lille University Hospital. GERAD/PERADES was supported by the Medical Research Council (Grant n° 503480), Alzheimer’s Research UK (Grant n° 503176), the Wellcome Trust (Grant n° 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant n° 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01–AG–12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer’s Association grant ADGC–10–196728.

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  1. School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Chris Ho Ching Yeung, Shiu Lun Au Yeung, Man Ki Kwok, Jie V. Zhao & C. Mary Schooling

  2. Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Chris Ho Ching Yeung

  3. Graduate School of Public Health and Health Policy, City University of New York, New York, USA

    C. Mary Schooling

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Contributions

CHCY, CMS and SLAY designed the study. All authors interpreted the results. CHCY conducted the analyses and wrote the first draft of the article with critical feedback and revision from CMS, SLAY, JVZ and MKK. All authors gave approval for the final version of the article for publication.

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Correspondence to Chris Ho Ching Yeung.

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Yeung, C., Au Yeung, S., Kwok, M.K. et al. The influence of growth and sex hormones on risk of alzheimer’s disease: a mendelian randomization study. Eur J Epidemiol 38, 745–755 (2023). https://doi.org/10.1007/s10654-023-01015-2

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