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The Impact of Testosterone on Alzheimer’s Disease Are Mediated by Lipid Metabolism and Obesity: A Mendelian Randomization Study

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The Journal of Prevention of Alzheimer's Disease Aims and scope Submit manuscript

Abstract

Background

To investigate the causal relationship between testosterone (BT) levels and Alzheimer’s disease (AD) risk and to quantify the role of obesity and lipid metabolism as potential mediators.

Methods

We used a two-sample, two-step MR to determine:1) the causal effect of BT levels on AD; 2) the causal effect of two lipid metabolites, obesity and LDLc on AD; and 3) the mediating effects of these metabolites. Pooled data for BT levels and lipid metabolism were obtained from the UK Biobank. AD data were obtained from the Alzheimer’s Disease Project International Genomics Consortium, FinnGen Consortium, and UK Biobank study. Effect estimates from external genome-wide association study (GWAS) pooled statistics were obtained using inverse variance-weighted (IVW) MR analysis.

Results

Higher levels of BT were associated with a reduced risk of AD (odds ratio [OR] 0.9992, 95% CI 0.9985–0.9998, P = 0.019), and there was a negative correlation with LDLc (OR 0.9208, 95% CI 0.8569–0.9895, P = 0.024) and obesity class 2 (OC2) (OR 0.7445, 95% CI 0.5873–0.9437, P = 0.014). Conversely, there was a positive correlation between LDLc (OR 1.0014, 95% CI 1.0000–1.0029, P = 0.043) and OC2 (OR 1.0005, 95% CI 1.0001–1.0009, P = 0.003) and AD. Mediation analysis showed that the indirect effect of BT levels on AD was achieved through LDLc and OC2, which accounted for 17% and 17% of the total effect, respectively.

Conclusion

Our study identified a causal role of BT levels in LDLc and OC2. BT levels may affect AD through LDLc and OC2 metabolic processes.

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Availability of data and materials: Data from the IEU OpenGWAS project (https://gwas.mrcieu.ac.uk/) are available for researchers to apply to individual cohorts through their website. All other data used are publicly available and cited according in the text.

Abbreviations

AD:

Alzheimer’s disease

BT:

Bioavailable testosterone

MR:

Mendelian randomization

GWAS:

Genome-wide association study

IVW:

Inverse variance-weighted

OR:

Odds ratio

LDLc:

LDL cholesterol

OC2:

Obesity class 2

Aβ:

β-amyloid

NHANES data:

National Health and Nutrition Examination Survey data

SNPs:

Single Nucleotide Polymorphisms

STROBE-MR:

Strengthening the Reporting of Observational Studies in Epidemiology-Mendelian Randomization

MVMR:

Multivariable Mendelian randomiza-tion

FTS:

F-statistic

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Funding

Funding: None.

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Authors and Affiliations

  1. Xi’an Hospital of Traditional Chinese Medicine, Guang’an men, Xi’an, 710021, Shaanxi, China

    L. Zhang, Y. Hu, M. Li, C. Wang, X. Chang & Lin Yang

  2. Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China

    F. Yang

  3. Shaanxi University of Traditional Chinese Medicine, First School of Clinical Medicine, Xianyang, 712046, Shaanxi, China

    J. Ma

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Contributions

Authors’ contributions: LLZ and LY initiated the study. LLZ undertook all statistical analysis. FY, JYM, and LY drafted the manuscript. XC, YXH, CW, and ML participated in the analysis. contributed to the interpretation of the analysis results and critical revision of the manuscript. LY managed the project. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Lin Yang.

Ethics declarations

Ethics approval and consent to participate: All data used in this study were obtained from published GWAS studies. And all participants in each study provided informed consent, and all studies were approved by the relevant institutional review boards. Therefore, ethical approval was not required for this study because no unauthorized data at the individual level were used.

Consent for publication: Not applicable.

Competing interests: The authors declare that they have no competing interests.

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Zhang, L., Yang, F., Ma, J. et al. The Impact of Testosterone on Alzheimer’s Disease Are Mediated by Lipid Metabolism and Obesity: A Mendelian Randomization Study. J Prev Alzheimers Dis 11, 507–513 (2024). https://doi.org/10.14283/jpad.2023.116

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