血源性线粒体 DNA 拷贝数与阿尔茨海默病、阿尔茨海默病相关生物标志物和血清代谢物有关。

IF 7.9 1区 医学 Q1 CLINICAL NEUROLOGY
Tong Tong, Congcong Zhu, John J Farrell, Zainab Khurshid, Eden R Martin, Margaret A Pericak-Vance, Li-San Wang, William S Bush, Gerard D Schellenberg, Jonathan L Haines, Wei Qiao Qiu, Kathryn L Lunetta, Lindsay A Farrer, Xiaoling Zhang
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引用次数: 0

摘要

背景:血源性线粒体 DNA 拷贝数(mtDNA-CN)是外周和中枢系统线粒体功能的替代测量指标。异常的 mtDNA-CN 不仅表明 mtDNA 复制和转录机制受损,还表明能量和脂质代谢等生物过程失调。然而,mtDNA-CN 与阿尔茨海默病(AD)之间的关系尚不清楚:我们利用公开的 mtDNA-CN 和 AD 的 GWAS 统计摘要进行了双样本孟德尔随机化(MR),以研究 mtDNA-CN 和 AD 之间的因果关系。我们利用阿尔茨海默病测序项目(Alzheimer's Disease Sequencing Project)中 13,799 人血液和大脑样本的全基因组序列数据估算了 mtDNA-CN。在评估mtDNA-CN与AD的关系时,采用了线性模型和Cox比例危险模型,并对年龄、性别和研究阶段进行了调整。在阿尔茨海默病神经影像倡议中,我们使用线性回归评估了AD生物标志物和血清代谢物与血液中mtDNA-CN的关联。我们进行了因果中介分析,以检验 mtDNA-CN 变化通过显著相关的生物标志物和代谢物对 AD 风险的自然间接影响:MR分析表明,血源性mtDNA-CN减少与AD风险增加之间存在因果关系(OR = 0.68; P = 0.013)。生存分析表明,mtDNA-CN 的减少与轻度认知障碍转化为 AD 的风险增加显著相关(HR = 0.80;P = 0.002)。我们还发现,mtDNA-CN 与脑 FDG-PET(β = 0.103;P = 0.022)、淀粉样蛋白-PET(β = 0.117;P = 0.034)、脑脊液淀粉样蛋白-β(Aβ)42/40(β=-0.124; P = 0.017)、女性 CSF t-Tau (β = 0.128; P = 0.015)、p-Tau (β = 0.140; P = 0.008) 和血浆 NFL (β=-0.124; P = 0.004)。血清中的几种脂质、氨基酸和生物胺也与 mtDNA-CN 显著相关。因果中介分析显示,mtDNA-CN对AD风险的影响约有三分之一是由血浆NFL中介的(P = 0.009),这种影响在女性中更为显著(P 结论:mtDNA-CN对AD风险的影响是由血浆NFL中介的:我们的研究表明,在血液中测量的 mtDNA-CN 可预测注意力缺失症,并与注意力缺失症生物标志物(包括血浆 NFL)相关,尤其是在女性中。此外,我们还说明,mtDNA-CN 的降低可能会通过线粒体脂质代谢和炎症的失调增加 AD 风险。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Blood-derived mitochondrial DNA copy number is associated with Alzheimer disease, Alzheimer-related biomarkers and serum metabolites.

Background: Blood-derived mitochondrial DNA copy number (mtDNA-CN) is a proxy measurement of mitochondrial function in the peripheral and central systems. Abnormal mtDNA-CN not only indicates impaired mtDNA replication and transcription machinery but also dysregulated biological processes such as energy and lipid metabolism. However, the relationship between mtDNA-CN and Alzheimer disease (AD) is unclear.

Methods: We performed two-sample Mendelian randomization (MR) using publicly available summary statistics from GWAS for mtDNA-CN and AD to investigate the causal relationship between mtDNA-CN and AD. We estimated mtDNA-CN using whole-genome sequence data from blood and brain samples of 13,799 individuals from the Alzheimer's Disease Sequencing Project. Linear and Cox proportional hazards models adjusting for age, sex, and study phase were used to assess the association of mtDNA-CN with AD. The association of AD biomarkers and serum metabolites with mtDNA-CN in blood was evaluated in Alzheimer's Disease Neuroimaging Initiative using linear regression. We conducted a causal mediation analysis to test the natural indirect effects of mtDNA-CN change on AD risk through the significantly associated biomarkers and metabolites.

Results: MR analysis suggested a causal relationship between decreased blood-derived mtDNA-CN and increased risk of AD (OR = 0.68; P = 0.013). Survival analysis showed that decreased mtDNA-CN was significantly associated with higher risk of conversion from mild cognitive impairment to AD (HR = 0.80; P = 0.002). We also identified significant associations of mtDNA-CN with brain FDG-PET (β = 0.103; P = 0.022), amyloid-PET (β = 0.117; P = 0.034), CSF amyloid-β (Aβ) 42/40 (β=-0.124; P = 0.017), CSF t-Tau (β = 0.128; P = 0.015), p-Tau (β = 0.140; P = 0.008), and plasma NFL (β=-0.124; P = 0.004) in females. Several lipid species, amino acids, biogenic amines in serum were also significantly associated with mtDNA-CN. Causal mediation analyses showed that about a third of the effect of mtDNA-CN on AD risk was mediated by plasma NFL (P = 0.009), and this effect was more significant in females (P < 0.005).

Conclusions: Our study indicates that mtDNA-CN measured in blood is predictive of AD and is associated with AD biomarkers including plasma NFL particularly in females. Further, we illustrate that decreased mtDNA-CN possibly increases AD risk through dysregulation of mitochondrial lipid metabolism and inflammation.

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来源期刊
Alzheimer's Research & Therapy
Alzheimer's Research & Therapy 医学-神经病学
CiteScore
13.10
自引率
3.30%
发文量
172
审稿时长
>12 weeks
期刊介绍: Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.
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