Rajendrakumar Aravind Lathika, Arbeev Konstantin G, Bagley Olivia, Yashin Anatoliy I, Ukraintseva Svetlana
Biodemography of Aging Research Unit, Duke University, Social Science Research Institute, Durham, NC, USA.
medRxiv. 2024 Jun 22:2024.06.21.24309310. doi: 10.1101/2024.06.21.24309310.
Emerging evidence suggests a connection between vulnerability to infections and Alzheimer's disease (AD). The nectin cell adhesion molecule 2 gene coding for a membrane component of adherens junctions is involved in response to infection, and its single nucleotide polymorphism (SNP) rs6859 was significantly associated with AD risk in several human cohorts. It is unclear, however, how exactly rs6859 influences the development of AD pathology. The aggregation of hyperphosphorylated tau protein (pTau) is a key pathological feature of neurodegeneration in AD, which may be induced by infections, among other factors, and potentially influenced by genes involved in both AD and vulnerability to infections, such as .
We conducted a causal mediation analysis (CMA) on a sample of 708 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The relationship between rs6859 and Alzheimer's disease (AD), with AD (yes/no) as the outcome and pTau-181 levels in the cerebrospinal fluid (CSF) acting as a mediator in this association, was assessed. Adjusted estimates from the probit and linear regression models were used in the CMA model, where an additive model considered an increase in dosage of the rs6859 A allele (AD risk factor).
The increase in dose of allele A of the SNP rs6859 resulted in about 0.144 increase per standard deviation (SD) of pTau-181 (95% CI: 0.041, 0.248, p<0.01). When included together in the probit model, the change in A allele dose and each standard deviation change in pTau-181 predicted 6.84% and 9.79% higher probabilities for AD, respectively. In the CMA, the proportion of the average mediated effect was 17.05% and was higher for the risk allele homozygotes (AA), at 19.40% (95% CI: 6.20%, 43.00%, p<0.01). The sensitivity analysis confirmed the evidence of a robust mediation effect.
This study reported a new causal relationship between pTau-181 and AD. We found that the association between rs6859 in the gene and AD is partly mediated by pTau-181 levels in CSF. The rest of this association may be mediated by other factors. Further research, using other biomarkers, is needed to uncover the remaining mechanisms of the association between the gene and AD.
新出现的证据表明，感染易感性与阿尔茨海默病（AD）之间存在联系。编码黏附连接膜成分的nectin细胞黏附分子2基因参与感染反应，其单核苷酸多态性（SNP）rs6859在多个人类队列中与AD风险显著相关。然而，尚不清楚rs6859究竟如何影响AD病理的发展。高磷酸化tau蛋白（pTau）的聚集是AD神经退行性变的关键病理特征，这可能由感染等因素诱导，并可能受到参与AD和感染易感性的基因的影响，例如。
我们对阿尔茨海默病神经影像学倡议（ADNI）的708名参与者样本进行了因果中介分析（CMA）。评估了rs6859与阿尔茨海默病（AD）之间的关系，以AD（是/否）为结局，脑脊液（CSF）中的pTau-181水平作为该关联的中介。CMA模型使用了来自概率单位和线性回归模型的调整估计值，其中加性模型考虑rs6859 A等位基因（AD风险因素）剂量的增加。
SNP rs6859的A等位基因剂量增加导致pTau-181每标准差（SD）增加约0.144（95%CI：0.041，0.248，p<0.01）。当一起纳入概率单位模型时，A等位基因剂量的变化和pTau-181每标准差变化分别预测AD的概率高6.84%和9.79%。在CMA中，平均中介效应的比例为17.05%，风险等位基因纯合子（AA）的比例更高，为19.40%（95%CI：6.20%，43.00%，p<0.01）。敏感性分析证实了存在稳健中介效应的证据。
本研究报告了pTau-18与AD之间的一种新的因果关系。我们发现基因中rs6859与AD之间的关联部分由CSF中的pTau-181水平介导。该关联的其余部分可能由其他因素介导。需要使用其他生物标志物进行进一步研究，以揭示该基因与AD之间关联的其余机制。
