Li Haonan, Cheng Meng, Zhang Nannan, Wang Siqi, Ye Caihua, Li Haodong, Wang Shengnan, Wang Zirui, Yang Xuan, Liu Zhixuan, Zhang Xingyu, Xu Jiayuan, Xu Qiang, Wang Junping
Department of Radiology, Tianjin Key Lab of Functional Imaging & Tianjin Institute of Radiology, Tianjin Medical University General Hospital, Tianjin 300052, China.
Medical School, Tianjin University, Tianjin 300072, China.
J Prev Alzheimers Dis. 2025 Jun;12(6):100155. doi: 10.1016/j.tjpad.2025.100155. Epub 2025 Apr 2.
Neurodegenerative diseases (NDs) lead to a progressive loss of neuronal cells and link to atrophy of subcortical brain structures, but the causal intermediates are not known. To test whether major NDs (Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis) causally affects subcortical atrophy, and whether serum vitamin level play a mediating role in this process.
Using large-scale genome-wide association study (GWAS) summary data, we performed two-sample Mendelian randomization (MR) to assess the causal effect of NDs on the volume of seven subcortical structures, and then adopted two-step multivariable MR approach to quantify the proportion of the effect of NDs on the volume of subcortical regions mediated by serum vitamin level. Finally, we utilized animal experiments to validate results and explored the potential molecular mechanisms.
Genetically predicted AD was associated with atrophy of the nucleus accumbens (NAc) (β = -0.09; p = 5.13 × 10), amygdala (β = -0.07; p = 8.44 × 10), and hippocampus (β = -0.07; p = 0.001), as well as with low serum vitamin D level (β = -0.02; p = 6.84 × 10). Specifically, decreased serum vitamin D level mediated 3.99 % (95 % CI: -0.006 to -5.82 × 10) and 3.97 % (95 % CI: -0.007 to -2.94 × 10) of the total effect of AD on hippocampal and NAc atrophy, respectively. Animal experiments further confirmed significant delays in hippocampal and NAc atrophy, a significant reduction of β-amyloid deposits and an increase of vitamin D receptor expression in hippocampus in AD mice with high-dose vitamin D diet.
These findings provide important insights into the effect sizes of vitamin D-mediated roles in AD and atrophy of subcortical structures. Interventions to increase serum vitamin D levels at a population level might attenuate damage to hippocampus in patients with AD.
神经退行性疾病（NDs）导致神经元细胞逐渐丧失，并与皮质下脑结构萎缩相关，但因果中间环节尚不清楚。为了检验主要的神经退行性疾病（阿尔茨海默病（AD）、帕金森病、多发性硬化症和肌萎缩侧索硬化症）是否因果性地影响皮质下萎缩，以及血清维生素水平在这一过程中是否起中介作用。
利用大规模全基因组关联研究（GWAS）汇总数据，我们进行了两样本孟德尔随机化（MR），以评估神经退行性疾病对七个皮质下结构体积的因果效应，然后采用两步多变量MR方法来量化血清维生素水平介导的神经退行性疾病对皮质下区域体积影响的比例。最后，我们利用动物实验验证结果并探索潜在的分子机制。
基因预测的AD与伏隔核（NAc）萎缩（β = -0.09；p = 5.13×10）、杏仁核（β = -0.07；p = 8.44×10）和海马体（β = -0.07；p = 0.001）相关，也与低血清维生素D水平相关（β = -0.02；p = 6.84×10）。具体而言，血清维生素D水平降低分别介导了AD对海马体和NAc萎缩总效应的3.99%（95%CI：-0.006至-5.82×10）和3.97%（95%CI：-0.007至-2.94×10）。动物实验进一步证实，高剂量维生素D饮食的AD小鼠海马体和NAc萎缩明显延迟，β-淀粉样蛋白沉积显著减少，海马体中维生素D受体表达增加。
这些发现为维生素D在AD和皮质下结构萎缩中的介导作用的效应大小提供了重要见解。在人群水平上提高血清维生素D水平的干预措施可能会减轻AD患者海马体的损伤。
