Abstract：
Dementia is a significant cause of elderly disability and Alzheimer\'s disease (AD) is the most prevalent form of dementia. As an early stage of AD, the mechanism related to mild cognitive impairment (MCI) and heavy metals is still unclear. This study utilized a cross-sectional design and enrolled 514 older adults in Bejing, China. Cognitive function was assessed by the Mini-Mental State Examination (MMSE) and fourteen blood metals were measured by inductively coupled plasma mass spectrometry (ICP-MS). In the adjusted single-metal models, we observed that copper [Cu, β (95% CI): 3.73 (-6.42, -1.03)] and lead [Pb, β (95% CI): 0.79 (-1.26, -0.32)] demonstrated negative associations with cognitive function, while selenium [Se, β (95% CI): 2.97 (1.23, 4.70)] was beneficial to cognition. Our findings were robust in secondary analysis using multi-metal models, which included generalized linear models (GLM), Bayesian kernel machine regression (BKMR), and quantile g-computation (qgcomp). Moreover, the toxic metal mixture (Cu and Pb) exhibited a significant negative association with MMSE scores and the inclusion of Se in the metal mixture attenuated the neurotoxicity of Cu-Pb mixture. The in silico analysis was used to examine the potential molecular mechanisms (genes, biological processes, pathways, and illnesses) of interaction among metal mixtures. We identified 20 cognition-related genes that are associated with both Cu-Pb and Se. Among these genes, eight (APOE, APP, BAX, BDNF, CASP3, HMOX1, TF, and TPP1) exhibited opposite effects on protein activity, mRNA expression, or protein expression in response to Se and Cu/Pb exposure, which could be the key genes accounting for the anti-neurotoxic effects of Se. Our findings support that Se can attenuate the neurotoxicity of exposure to single Cu or Pb, and Cu-Pb mixture. More research is needed to confirm our findings and gain knowledge about the molecular mechanisms of combined metal exposure on cognitive function.
摘要：
痴呆是导致老年人残疾的重要原因,而阿尔茨海默病(AD)是痴呆的最常见形式。作为AD的早期阶段，与轻度认知障碍（MCI）和重金属相关的机制尚不清楚。本研究采用横断面设计，招募了514名北京老年人，中国。通过迷你精神状态检查（MMSE）评估认知功能，并通过电感耦合等离子体质谱法（ICP-MS）测量14种血液金属。在调整后的单金属模型中，我们观察到铜[铜，β（95%CI）：3.73（-6.42，-1.03）]和铅[Pb，β（95%CI）：0.79（-1.26，-0.32）]显示与认知功能呈负相关，而硒[Se，β（95%CI）：2.97（1.23，4.70）]对认知有益。我们的发现在使用多金属模型的二次分析中是稳健的，其中包括广义线性模型(GLM)，贝叶斯核机回归(BKMR)，和分位数g计算(qgcomp)。此外，有毒金属混合物（Cu和Pb）与MMSE评分呈显着的负相关，并且在金属混合物中包含Se会减弱Cu-Pb混合物的神经毒性。计算机模拟分析用于检查潜在的分子机制(基因，生物过程，通路,和疾病)金属混合物之间的相互作用。我们确定了20个与Cu-Pb和Se相关的认知相关基因。在这些基因中,八（APOE，APP,巴克斯，BDNF,CASP3,HMOX1,TF,和TPP1）对蛋白质活性表现出相反的作用，mRNA表达，或响应Se和Cu/Pb暴露的蛋白质表达，这可能是解释硒抗神经毒性作用的关键基因。我们的发现支持硒可以减弱暴露于单一铜或铅的神经毒性，和Cu-Pb混合物。需要更多的研究来证实我们的发现，并获得有关联合金属暴露对认知功能的分子机制的知识。
