Xingzhi Guo, Wenzhi Shi, Juanjuan Lu, Peng Tang, Rui Li
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Three distinct AD genome-wide association study (GWAS) data sets from the International Genomics of Alzheimer's Project (IGAP), UK Biobank (UKB), and FinnGen were utilized. Summary-level data on blood sRANKL and OPG were sourced from deCODE Genetics.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>Genetically predicted per standard deviation (SD) increase in blood sRANKL levels was significantly associated with a reduced risk of AD across all three AD GWAS data sets (IGAP: odds ratio [OR] = 0.82, 95% confidence interval [CI] = 0.72–0.94, <i>p</i> = 0.004; UKB: OR = 0.85, 95% CI = 0.78–0.91, <i>p</i> < 0.001; FinnGen: OR = 0.83, 95% CI = 0.73–0.94, <i>p</i> = 0.004). No significant causal relationship was observed between OPG levels and AD. In addition, there was no causal impact of AD on the blood levels of sRANKL and OPG. MVMR results showed that the inverse association between sRANKL and AD risk persisted after adjusting for BMD and interleukin-1α and chemoattractant protein-1.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>Our study provides evidence that elevated sRANKL levels are causally linked to a reduced risk of AD, independent of BMD and inflammation. 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引用次数: 0
摘要
观察性研究揭示了骨密度（BMD）降低与阿尔茨海默病（AD）风险之间的密切关系。核因子κ b配体受体激活剂（RANKL）和骨保护素（OPG）系统在调节骨代谢中起关键作用，已被认为与脑功能有关，但其对AD风险的因果影响尚不清楚。方法：我们采用双向孟德尔随机化（MR）和多变量MR （MVMR）方法来阐明血溶性RANKL （sRANKL）和OPG水平对AD的影响，评估这种影响是否独立于BMD和炎症。三个不同的AD全基因组关联研究（GWAS）数据集分别来自国际阿尔茨海默氏症基因组计划（IGAP）、英国生物银行（UKB）和FinnGen。血液sRANKL和OPG的汇总数据来自deCODE Genetics。结果：在所有三个AD GWAS数据集中，遗传预测的每标准差（SD）血中sRANKL水平升高与AD风险降低显著相关(IGAP：优势比[OR] = 0.82, 95%可信区间[CI] = 0.72-0.94, p = 0.004；UKB: OR = 0.85, 95% CI = 0.78-0.91, p < 0.001；FinnGen:或= 0.83,95% CI -0.94 = 0.73, p = 0.004)。OPG水平与AD之间没有明显的因果关系。此外，AD对血液中sRANKL和OPG水平没有因果影响。MVMR结果显示，在调整BMD、白细胞介素-1α和趋化蛋白-1后，sRANKL与AD风险的负相关关系仍然存在。讨论：我们的研究提供了证据，表明升高的sRANKL水平与AD风险降低有因果关系，与BMD和炎症无关。这些发现增强了我们对骨代谢和AD之间复杂相互作用的理解。重点：血溶性受体激活物核因子κ b配体（sRANKL）水平与阿尔茨海默病（AD）风险降低有关。sRANKL水平与AD之间的关联与骨密度（BMD）和炎症无关。血液中骨保护素水平与AD之间不存在因果关系。AD不影响血液中sRANKL或骨保护素的水平。
Unraveling the impact of blood RANKL and OPG levels on Alzheimer's disease: Independent of bone mineral density and inflammation
INTRODUCTION
Observational studies have revealed a close relationship between reduced bone mineral density (BMD) and Alzheimer's disease (AD) risk. The receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) system, pivotal in regulating bone metabolism, has been implicated in brain function, but the causal impact on AD risk remains unclear.
METHODS
We employed bi-directional Mendelian randomization (MR) and multivariable MR (MVMR) approaches to elucidate the effect of blood soluble RANKL (sRANKL) and OPG levels on AD, assessing whether this influence was independent of BMD and inflammation. Three distinct AD genome-wide association study (GWAS) data sets from the International Genomics of Alzheimer's Project (IGAP), UK Biobank (UKB), and FinnGen were utilized. Summary-level data on blood sRANKL and OPG were sourced from deCODE Genetics.
RESULTS
Genetically predicted per standard deviation (SD) increase in blood sRANKL levels was significantly associated with a reduced risk of AD across all three AD GWAS data sets (IGAP: odds ratio [OR] = 0.82, 95% confidence interval [CI] = 0.72–0.94, p = 0.004; UKB: OR = 0.85, 95% CI = 0.78–0.91, p < 0.001; FinnGen: OR = 0.83, 95% CI = 0.73–0.94, p = 0.004). No significant causal relationship was observed between OPG levels and AD. In addition, there was no causal impact of AD on the blood levels of sRANKL and OPG. MVMR results showed that the inverse association between sRANKL and AD risk persisted after adjusting for BMD and interleukin-1α and chemoattractant protein-1.
DISCUSSION
Our study provides evidence that elevated sRANKL levels are causally linked to a reduced risk of AD, independent of BMD and inflammation. These findings enhance our understanding of the complex interactions between bone metabolism and AD.
Highlights
Blood soluble receptor activator of nuclear factor kappa-B ligand (sRANKL) levels are linked to a reduced risk of Alzheimer's disease (AD).
The association between sRANKL levels and AD is independent of bone mineral density (BMD) and inflammation.
No causal link exists between blood osteoprotegerin levels and AD.
AD does not affect blood levels of sRANKL or osteoprotegerin.
期刊介绍：
Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.
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