Department of Geriatric Neurology, Shaanxi Provincial People's Hospital, Xi'an, 710068, Shaanxi, China.
Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China.
Transl Psychiatry. 2024 May 20;14(1):205. doi: 10.1038/s41398-024-02924-w.
Growing evidence suggests an association between osteocalcin (OCN), a peptide derived from bone and involved in regulating glucose and lipid metabolism, and the risk of Alzheimer's disease (AD). However, the causality of these associations and the underlying mechanisms remain uncertain. We utilized a Mendelian randomization (MR) approach to investigate the causal effects of blood OCN levels on AD and to assess the potential involvement of glucose and lipid metabolism. Independent instrumental variables strongly associated (P < 5E-08) with blood OCN levels were obtained from three independent genome-wide association studies (GWAS) on the human blood proteome (N = 3301 to 35,892). Two distinct summary statistics datasets on AD from the International Genomics of Alzheimer's Project (IGAP, N = 63,926) and a recent study including familial-proxy AD patients (FPAD, N = 472,868) were used. Summary-level data for fasting glucose (FG), 2h-glucose post-challenge, fasting insulin, HbA1c, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol (TC), and triglycerides were incorporated to evaluate the potential role of glucose and lipid metabolism in mediating the impact of OCN on AD risk. Our findings consistently demonstrate a significantly negative correlation between genetically determined blood OCN levels and the risk of AD (IGAP: odds ratio [OR, 95%CI] = 0.83[0.72-0.96], P = 0.013; FPAD: OR = 0.81 [0.70-0.93], P = 0.002). Similar estimates with the same trend direction were obtained using other statistical approaches. Furthermore, employing multivariable MR analysis, we found that the causal relationship between OCN levels and AD was disappeared after adjustment of FG and TC (IGAP: OR = 0.97[0.80-1.17], P = 0.753; FPAD: OR = 0.98 [0.84-1.15], P = 0.831). There were no apparent instances of horizontal pleiotropy, and leave-one-out analysis showed good stability of the estimates. Our study provides evidence supporting a protective effect of blood OCN levels on AD, which is primarily mediated through regulating FG and TC levels. Further studies are warranted to elucidate the underlying physio-pathological mechanisms.
越来越多的证据表明，骨钙素（OCN）与阿尔茨海默病（AD）的风险之间存在关联。OCN 是一种源自骨骼并参与调节葡萄糖和脂质代谢的肽。然而，这些关联的因果关系和潜在机制尚不确定。我们利用孟德尔随机化（MR）方法研究了血液 OCN 水平对 AD 的因果影响，并评估了葡萄糖和脂质代谢的潜在作用。从人类血液蛋白质组的三项独立全基因组关联研究（GWAS）中获得了与血液 OCN 水平强烈相关（P<5E-08）的独立工具变量（N=3301 至 35892）。国际阿尔茨海默病基因组学项目（IGAP，N=63926）和包括家族性代理 AD 患者的最近一项研究（FPAD，N=472868）的两项不同的 AD 综合统计数据集被用于分析。纳入空腹血糖（FG）、2 小时葡萄糖后挑战、空腹胰岛素、HbA1c、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、总胆固醇（TC）和甘油三酯的汇总水平数据，以评估 OCN 对 AD 风险的影响通过葡萄糖和脂质代谢的潜在作用。我们的研究结果一致表明，遗传决定的血液 OCN 水平与 AD 风险之间呈显著负相关（IGAP：比值比[OR，95%CI] = 0.83[0.72-0.96]，P=0.013；FPAD：OR=0.81 [0.70-0.93]，P=0.002）。使用其他统计方法也得到了相同趋势方向的相似估计值。此外，采用多变量 MR 分析，我们发现 OCN 水平与 AD 之间的因果关系在调整 FG 和 TC 后消失（IGAP：OR=0.97[0.80-1.17]，P=0.753；FPAD：OR=0.98 [0.84-1.15]，P=0.831）。没有明显的水平多效性实例，单因素分析表明估计值具有良好的稳定性。我们的研究提供了支持血液 OCN 水平对 AD 具有保护作用的证据，这主要是通过调节 FG 和 TC 水平来实现的。需要进一步的研究来阐明潜在的生理病理机制。
