Guo Xingzhi, Shi Wenzhi, Lu Juanjuan, Tang Peng, Li Rui
Department of Geriatric Neurology Shaanxi Provincial People's Hospital Xi'an Shaanxi China.
Department of Geriatric Neurology the Third Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi China.
Alzheimers Dement (N Y). 2025 Jan 20;11(1):e70044. doi: 10.1002/trc2.70044. eCollection 2025 Jan-Mar.
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.
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.
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, = 0.004; UKB: OR = 0.85, 95% CI = 0.78-0.91, < 0.001; FinnGen: OR = 0.83, 95% CI = 0.73-0.94, = 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.
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.
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.
观察性研究表明，骨矿物质密度（BMD）降低与阿尔茨海默病（AD）风险之间存在密切关系。核因子κB受体激活剂配体（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。
我们采用双向孟德尔随机化（MR）和多变量MR（MVMR）方法，以阐明血液中可溶性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。使用了来自国际阿尔茨海默病基因组计划（IGAP）、英国生物银行（UKB）和芬兰基因库的三个不同的AD全基因组关联研究（GWAS）数据集。血液中sRANKL和OPG的汇总水平数据来自 deCODE Genetics。
在所有三个AD GWAS数据集中，基因预测的血液sRANKL水平每增加一个标准差（SD），与AD风险降低显著相关（IGAP：比值比[OR]=0.82，95%置信区间[CI]=0.72-0.94，P=0.004；UKB：OR=0.85，95%CI=0.78-0.91，P<0.001；芬兰基因库：OR=0.83，95%CI=0.73-0.94，P=0.004）。未观察到OPG水平与AD之间存在显著的因果关系。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和趋化因子蛋白-1后，sRANKL与AD风险之间的负相关仍然存在。
我们的研究提供了证据，表明sRANKL水平升高与AD风险降低存在因果关系，且独立于BMD和炎症。这些发现加深了我们对骨代谢与AD之间复杂相互作用的理解。
血液中核因子κB受体激活剂可溶性配体（sRANKL）水平与阿尔茨海默病（AD）风险降低有关。sRANKL水平与AD之间的关联独立于骨矿物质密度（BMD）和炎症。血液中骨保护素水平与AD之间不存在因果联系。AD不影响血液中sRANKL或骨保护素水平。
