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

IF 8.5 3区医学 Q1 CLINICAL NEUROLOGY

Jpad-Journal of Prevention of Alzheimers Disease Pub Date : 2024-01-01 DOI:10.14283/jpad.2023.116

L Zhang, F Yang, J Ma, Y Hu, M Li, C Wang, X Chang, L Yang

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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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睾酮对阿尔茨海默病的影响受脂质代谢和肥胖的介导：孟德尔随机研究》。

背景：研究睾酮（BT）水平与阿尔茨海默病（AD）风险之间的因果关系，并量化肥胖和脂质代谢作为潜在介质的作用：我们采用双样本、双步骤 MR 方法来确定：1）BT 水平对 AD 的因果效应；2）肥胖和 LDLc 这两种脂质代谢物对 AD 的因果效应；3）这些代谢物的中介效应。BT水平和脂质代谢的汇总数据来自英国生物库。注意力缺失症数据来自阿尔茨海默病项目国际基因组学联合会、FinnGen 联合会和英国生物库研究。利用反方差加权（IVW）MR分析法从外部全基因组关联研究（GWAS）汇总统计中获得了效应估计值：BT水平越高，AD风险越低（几率比[OR]0.9992，95% CI 0.9985-0.9998，P = 0.019），与LDLc（OR 0.9208，95% CI 0.8569-0.9895，P = 0.024）和肥胖等级2（OC2）（OR 0.7445，95% CI 0.5873-0.9437，P = 0.014）呈负相关。相反，LDLc（OR 1.0014，95% CI 1.0000-1.0029，P = 0.043）和 OC2（OR 1.0005，95% CI 1.0001-1.0009，P = 0.003）与 AD 之间存在正相关。中介分析显示，BT水平对AD的间接影响是通过LDLc和OC2实现的，它们分别占总影响的17%和17%：结论：我们的研究确定了 BT 水平在 LDLc 和 OC2 中的因果作用。结论：我们的研究确定了 BT 水平在 LDLc 和 OC2 中的因果作用，BT 水平可能通过 LDLc 和 OC2 代谢过程影响 AD。

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来源期刊

Jpad-Journal of Prevention of Alzheimers Disease CLINICAL NEUROLOGY-

自引率

7.80%

发文量

期刊介绍： The JPAD « Journal of Prevention of Alzheimer’Disease » will publish reviews, original research articles and short reports to improve our knowledge in the field of Alzheimer prevention including : neurosciences, biomarkers, imaging, epidemiology, public health, physical cognitive exercise, nutrition, risk and protective factors, drug development, trials design, and heath economic outcomes. JPAD will publish also the meeting abstracts from Clinical Trial on Alzheimer Disease (CTAD) and will be distributed both in paper and online version worldwide.