Exploring mechanisms driving microbe-induced AD risk using next generation sequence data.

多条证据表明，微生物感染是阿尔茨海默病(AD)的危险因素。淀粉样蛋白-β (aβ)多肽具有抗菌活性，可能对人类疱疹病毒具有保护作用。病毒DNA 在β斑块中也可以检测到，在下一代测序实验中检测到的HHVDNA是 与AD风险相关。尽管神经炎症被认为是推动这种联系的机制， 还有几个问题仍然存在。最重要的是，目前还不清楚感染是在AD之前还是衰老的结果 免疫系统或AD病理本身。受感染影响的AD病理的具体方面有 宿主基因组在调节风险中的作用也是未知的。这个项目的目标是回答 通过利用来自血液和大脑样本的NGS数据来利用大型AD队列来检测这些问题 微生物DNA的存在。微生物DNA可以在人类NGS实验中通过以下方法检测和定量 将未映射到人类基因组的读数与微生物参考基因组进行比对，并根据 已识别的物种，可能是活跃或潜伏感染的证据。任何微生物，其参照物 可以检测到基因组是否可用。这些队列包括阿尔茨海默病测序项目 (ADSP)、阿尔茨海默病神经成像倡议(ADNI)、弗雷明翰心脏研究(FHS)、 加速药物合作-阿尔茨海默病(AMP-AD)和光州阿尔茨海默氏症及相关 痴呆项目(GARD)。该项目的长期目标是提供证据，证明干预措施针对 微生物感染可以预防阿尔茨海默病或减缓其进展。我们的中心假设是感染增加 AD风险，并对AD病理的特定方面造成可观察的变化。我们还假设， 人类基因组参与了这些过程。我们将通过以下具体实例来检验这些假设 目标。在Aim1中，我们将开发一条管道，以准确量化和匹配Next产生的DNA片段 对微生物DNA序列进行世代测序，包括插入的病毒DNA。在AIM2中，我们将利用 用多组学数据纵向跟踪队列，建立感染和感染之间的时间关系 AD，并测试微生物DNA与AD相关特征之间的关联，包括生物标记物、结构 磁共振成像测量的脑变化，神经病理特征，疾病进展，脑 细胞类型、亚组分、认知功能。在Aim3中，我们探索了宿主基因组在调节 微生物诱导的阿尔茨海默病病理，包括SNPs和微生物之间的相关性测试，以及 已知的AD风险变异体/人类白细胞抗原血清型和微生物DNA之间的相互作用预测AD。这个项目是 意义重大，因为它可以提供证据，证明预防或治疗感染可以治疗或预防阿尔茨海默病。 该项目具有创新性，因为它将是第一个利用非常大的AD NGS队列的项目，其中许多 用于DNA测序的组织是在AD诊断之前收集的，并使用仅病例分析来联系 微生物DNA对AD病理的特定方面。

Multiple lines of evidence suggest microbial infections are risk factors for Alzheimer’s disease (AD). Amyloid-β (Aβ) peptides possess antimicrobial activity and may protect against human herpes viruses (HHV). Viral DNA is also detectable in Aβ plaques, and HHV DNA detected in next generation sequencing (NGS) experiments is associated with AD risk. Although neuroinflammation is the mechanism assumed to drive this association, several questions remain. Foremost, it is unclear whether infections precede AD or are the result of an aging immune system or AD pathology itself. The specific aspects of AD pathology that are affected by infections are also unknown, as is the role of the host genome in mediating risk. The objective of this project is to answer these questions by leveraging large AD cohorts with NGS data derived from blood and brain samples to detect the presence of microbial DNA. Microbial DNA can be detected and quantified in human NGS experiments by aligning reads that do not map to the human genome to microbial reference genomes, and depending on the species identified, may be evidence of either an active or latent infection. Any microbe for which a reference genome is available can be detected. The cohorts include the Alzheimer’s Disease Sequencing Project (ADSP), the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Framingham Heart Study (FHS), Accelerating Medicines Partnership-Alzheimer's Disease (AMP-AD), and Gwangju Alzheimer's & Related Dementias project (GARD). The long-term goal of this project is to provide evidence that interventions targeting microbial infections could prevent AD or slow its progression. Our central hypothesis is that infections increase AD risk and cause observable changes to specific facets of AD pathology. We also hypothesize that variants in the human genome mediate these processes. We will test these hypotheses through the following specific aims. In Aim1, we will develop a pipeline to accurately quantify and match DNA fragments generated by next generation sequencing to microbial DNA sequences, including inserted viral DNA. In Aim2, we will leverage longitudinally followed cohorts with multi-omics data to establish a temporal relationship between infection and AD, and test for associations between microbial DNA and AD-related traits, including biomarkers, structural brain changes measured by magnetic resonance imaging, neuropathological traits, disease progression, brain cell type sub-fractions, and cognitive function. In Aim3, we explore the role of the host genome in mediating microbe induced AD pathology, including testing for associations between SNPs and microbes, and for interactions between known AD risk variants/HLA serotypes and microbial DNA to predict AD. This project is significant because it could provide evidence that preventing or treating infections could treat or prevent AD. The project is innovative because it will be the first to leverage very large AD NGS cohorts, in many of which the tissue used for DNA sequencing was collected prior to AD diagnosis, and use case-only analysis to link microbial DNA to specific aspects of AD pathology.