Xiao Qianyi, Xi Jianxiong, Wang Ruru, Zhao Qianhua, Liang Xiaoniu, Wu Wanqing, Zheng Li, Guo Qihao, Hong Zhen, Fu Hua, Ding Ding
Department of Preventive Medicine and Health Education, School of Public Health, Fudan University, Shanghai, China.
Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
Front Genet. 2022 Feb 21;13:823406. doi: 10.3389/fgene.2022.823406. eCollection 2022.
Genome-wide association studies have identified many Alzheimer's disease (AD) genetic-risk single nucleotide polymorphisms (SNPs) and indicated the important role of the cholesterol/lipid metabolism pathway in AD pathogenesis. This study aims to investigate the effects of cholesterol and genetic risk factors on progression of mild cognitive impairment (MCI) to AD. We prospectively followed 316 MCI participants aged ≥50 years with a baseline cholesterol profile and SNP genotyping data for 4.5 years on average in a sub-cohort of the Shanghai Aging Study. Total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol in serum were measured at baseline. SNP genotyping was performed using a MassARRAY system. At follow-up, consensus diagnosis of incident dementia and AD were established based on medical, neurological, and neuropsychological examinations. Cox regression models were used to assess the association of cholesterol and SNP with incident AD. The AG/AA genotypes of rs6859 were significantly associated with increased incident AD in MCI participants, compared with GG genotype (adjusted hazard ratio [HR] 2.75, 95% confidence interval [CI] 1.32-5.76, = .007, false discovery rate-adjusted = .030). In rs6859 AG/AA carriers, each-1 mmol/L higher level of LDL-C was significantly associated with a 48% decreased risk of AD (adjusted HR 0.52, 95%CI 0.33-0.84, = .007). Consistent results were obtained when using LDL-C as the categorical variable ( for trend = 0.016). The relationship between LDL-C and progression of MCI may be influenced by genetic variants.
全基因组关联研究已经鉴定出许多阿尔茨海默病（AD）的遗传风险单核苷酸多态性（SNP），并表明胆固醇/脂质代谢途径在AD发病机制中具有重要作用。本研究旨在探讨胆固醇和遗传风险因素对轻度认知障碍（MCI）进展为AD的影响。我们在上海老龄化研究的一个亚队列中，对316名年龄≥50岁、具有基线胆固醇谱和SNP基因分型数据的MCI参与者进行了平均4.5年的前瞻性随访。在基线时测量血清中的总胆固醇、低密度脂蛋白胆固醇（LDL-C）和高密度脂蛋白胆固醇。使用MassARRAY系统进行SNP基因分型。在随访时，基于医学、神经学和神经心理学检查对新发痴呆和AD进行一致性诊断。使用Cox回归模型评估胆固醇和SNP与新发AD的关联。与GG基因型相比，rs6859的AG/AA基因型与MCI参与者中AD发病率增加显著相关（调整后的风险比[HR]为2.75，95%置信区间[CI]为1.32 - 5.76，P = 0.007，错误发现率调整后P = 0.030）。在rs6859的AG/AA携带者中，LDL-C每升高1 mmol/L，AD风险显著降低48%（调整后的HR为0.52，95%CI为0.33 - 0.84，P = 0.007）。当使用LDL-C作为分类变量时，也获得了一致的结果（趋势P = 0.016）。LDL-C与MCI进展之间的关系可能受基因变异的影响。
