Duan Qing-Qing, Su Wei-Ming, Gu Xiao-Jing, Long Jiang, Jiang Zheng, Yin Kang-Fu, Cai Wei-Chen, Cao Bei, Chi Li-Yi, Gao Xia, Li Ju-Rong, Chen Yong-Ping
Department of Neurology, Centre for Rare diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Mental Health Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Brain Behav. 2025 Aug;15(8):e70766. doi: 10.1002/brb3.70766.
The incidence of neurodegenerative disorders (NDDs) is increasing, and currently, there are no curative treatments available for these conditions. The potential benefits of supplementation with diet-derived antioxidants and their metabolites for NDDs remain a subject of debate. In this study, we employed a two-sample Mendelian randomization (MR) analysis to investigate the potential causal relationship between elevated circulating antioxidant levels and the risk of NDDs.
We used single-nucleotide polymorphisms (SNPs) related to diet-derived antioxidants and p < 1E-05 as instrumental variables (IVs). The NDDs we studied included Parkinson's disease (PD) (33,674 cases and 449,056 controls), Alzeimers disease (AD) (111,326 cases and 677,663 controls), amyotrophic lateral sclerosis (ALS) (27,205 cases and 110,881 controls), and frontotemporal dementia (FTD) (3526 cases and 9402 controls) from GWASs conducted in the European descent. Two-sample MR was performed together with a series of sensitivity analyses. The main statistical analyses were conducted using the package "TwoSampleMR (V.0.5.6)" in R (V.4.2.0).
Genetically predicted levels of α-tocopherol and carotene were found to be associated with a reduced risk of ALS, with odds ratios (OR) of 0.45 (95% confidence interval [CI]: 0.31, 0.66; p = 3.97 × 10^-5) and 0.82 (95% CI: 0.68, 0.99; p = 0.0427), respectively. Similarly, vitamin E (OR 0.70; [95% CI 0.50, 0.98]; p = 0.0358) and ascorbate (OR 0.85; [95% CI: 0.73, 0.98]; p = 0.0216) demonstrated a protective effect against PD. Furthermore, elevated levels of retinol were associated with a reduced incidence of FTD, with an OR of 0.92 (95% CI: 0.86, 0.99; p = 0.0196), although they were also linked to an increased risk of ALS (OR 1.02 [95% CI 1.01, 1.04], p = 0.0017) and PD (OR 1.06 [95% CI 1.02, 1.09], p = 0.0121). No significant causal association was observed between circulating antioxidants and AD.
This MR study indicated a potential protective effect of α-tocopherol and carotene on ALS, vitamin E and ascorbate on PD, and retinol on FTD, while also identifying retinol as a risk factor for ALS and PD. These findings could contribute to the exploration of dietary therapies for NDDs. Further research is necessary to substantiate the potential associations between diet-derived antioxidants or their metabolites and the risk of NDDs in individuals.
神经退行性疾病（NDDs）的发病率正在上升，目前尚无针对这些疾病的治愈性疗法。饮食来源的抗氧化剂及其代谢产物补充剂对NDDs的潜在益处仍是一个有争议的话题。在本研究中，我们采用两样本孟德尔随机化（MR）分析来研究循环抗氧化剂水平升高与NDDs风险之间的潜在因果关系。
我们使用与饮食来源的抗氧化剂相关且p<1E-05的单核苷酸多态性（SNPs）作为工具变量（IVs）。我们研究的NDDs包括帕金森病（PD）（33674例病例和449056例对照）、阿尔茨海默病（AD）（111326例病例和677663例对照）、肌萎缩侧索硬化症（ALS）（27205例病例和110881例对照）以及额颞叶痴呆（FTD）（3526例病例和9402例对照），这些数据来自对欧洲血统人群进行的全基因组关联研究（GWASs）。进行了两样本MR分析以及一系列敏感性分析。主要统计分析使用R（V.4.2.0）中的“TwoSampleMR（V.0.5.6）”软件包进行。
发现遗传预测的α-生育酚和胡萝卜素水平与ALS风险降低相关，优势比（OR）分别为0.45（95%置信区间[CI]：0.31，0.66；p = 3.97×10^-5）和0.82（95%CI：0.68，0.99；p = 0.0427）。同样，维生素E（OR 0.70；[95%CI 0.50，0.98]；p = 0.0358）和抗坏血酸（OR 0.85；[95%CI：0.73，0.98]；p = 0.0216）对PD具有保护作用。此外，视黄醇水平升高与FTD发病率降低相关，OR为0.92（95%CI：0.86，0.99；p = 0.0196），尽管它也与ALS风险增加（OR 1.02 [95%CI 1.01，1.04]，p = 0.0017）和PD风险增加（OR 1.06 [95%CI 1.02，1.09]，p = 0.0121）有关。未观察到循环抗氧化剂与AD之间存在显著的因果关联。
这项MR研究表明α-生育酚和胡萝卜素对ALS、维生素E和抗坏血酸对PD以及视黄醇对FTD具有潜在保护作用，同时也确定视黄醇是ALS和PD的一个风险因素。这些发现可能有助于探索NDDs的饮食疗法。有必要进一步研究以证实饮食来源的抗氧化剂或其代谢产物与个体NDDs风险之间的潜在关联。
