Yang Ze, Sheng Jinhua, Zhang Qiao, Chou Jay Tsai Chien, Xin Yu, Wang Luyun
School of Computer Science and Technology, Hangzhou Dianzi University, Hangzhou, 310018, Zhejiang, China.
Key Laboratory of Intelligent Image Analysis for Sensory and Cognitive Health, Ministry of Industry and Information Technology of P. R. China, Hangzhou, 310018, Zhejiang, China.
Sci Rep. 2025 May 15;15(1):16838. doi: 10.1038/s41598-025-01927-x.
CD33 rs3865444 polymorphism is closely associated with the risk of Alzheimer's disease (AD), and CD33 is part of the sialic acid-binding Ig-superfamily of lectins (SIGLECs). Immunostaining experiments in previous studies have confirmed the expression of CD33 in human brain microglial cells, and an increase in CD33 mRNA expression in the brain microglial cells of patients with cognitive impairment has been observed. The minor allele CD33 rs3865444 (A) has a protective effect against Alzheimer's disease pathology and is associated with reduced CD33 expression and clearance of amyloid-beta plaques. The risk allele CD33 rs3865444 (C) can cause abnormal activation of microglial cells, thereby inducing neuroinflammation, accompanied by an increase in metabolic levels. We hypothesize that the CD33 rs3865444 polymorphism may affect the coupling between glucose metabolism and neuronal activity, thereby influencing individual cognitive trajectories and the progression of cognitive impairment. In this study, we included 107 patients with mild cognitive impairment, among whom the limbic-orbital frontal cortex glucose-oxygen coupling (G/O) coefficient of the CD33 rs3865444 CC group was significantly reduced. Additionally, the results of the mediation analysis showed that the glucose-oxygen coupling coefficient completely mediated the effect of the CD33 rs3865444 polymorphism on the rate of clinical dementia rating increase.
CD33 rs3865444基因多态性与阿尔茨海默病（AD）风险密切相关，且CD33是唾液酸结合免疫球蛋白超家族凝集素（SIGLECs）的一部分。既往研究中的免疫染色实验已证实CD33在人脑海马小胶质细胞中表达，且观察到认知障碍患者脑海马小胶质细胞中CD33 mRNA表达增加。CD33 rs3865444的次要等位基因（A）对阿尔茨海默病病理具有保护作用，并与CD33表达降低及β淀粉样蛋白斑块清除有关。风险等位基因CD33 rs3865444（C）可导致小胶质细胞异常激活，从而诱发神经炎症，并伴有代谢水平升高。我们推测，CD33 rs3865444基因多态性可能影响葡萄糖代谢与神经元活动之间的耦合，进而影响个体认知轨迹及认知障碍的进展。在本研究中，我们纳入了107例轻度认知障碍患者，其中CD33 rs3865444 CC组的边缘-眶额皮质葡萄糖-氧耦合（G/O）系数显著降低。此外，中介分析结果表明，葡萄糖-氧耦合系数完全介导了CD33 rs3865444基因多态性对临床痴呆评定量表增加率的影响。
