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

多种证据表明微生物感染是阿尔茨海默病（AD）的危险因素。β淀粉样蛋白 （Aβ）肽具有抗微生物活性，并且可以保护免受人类疱疹病毒（HHV）的侵害。病毒DNA 在Aβ斑块中也可检测到，在下一代测序（NGS）实验中检测到的HHV DNA， 与AD风险有关。虽然神经炎症是驱动这种关联的机制， 还有几个问题。最重要的是，目前还不清楚感染是在AD之前发生的，还是衰老的结果。 免疫系统或AD病理学本身。受感染影响的AD病理学的具体方面是 同样未知的是宿主基因组在介导风险中的作用。这个项目的目的是回答 这些问题通过利用来自血液和大脑样本的NGS数据的大型AD队列来检测 微生物DNA的存在。微生物DNA可以在人NGS实验中检测和定量， 将不映射到人类基因组的读段与微生物参考基因组进行比对，并且取决于所述微生物参考基因组， 鉴定的物种，可能是活动性或潜伏性感染的证据。任何微生物， 基因组是可以检测到的。这些研究小组包括阿尔茨海默病测序项目 （ADSP），阿尔茨海默病神经影像学倡议（ADNI），心脏病研究（FHS）， 加速药物合作-阿尔茨海默病（AMP-AD）和光州阿尔茨海默病及相关疾病 痴呆症项目。该项目的长期目标是提供证据，证明针对 微生物感染可以预防AD或减缓其进展。我们的中心假设是感染增加 AD风险和导致AD病理学特定方面的可观察变化。我们还假设， 人类基因组介导这些过程。我们将通过以下具体步骤来检验这些假设： 目标。在Aim 1中，我们将开发一个管道来精确地量化和匹配下一个生成的DNA片段。 对微生物DNA序列进行世代测序，包括插入的病毒DNA。在目标2中，我们将利用 用多组学数据纵向跟踪队列，以建立感染和 AD，并测试微生物DNA和AD相关性状之间的关联，包括生物标志物，结构 通过磁共振成像测量的脑变化，神经病理学特征，疾病进展，脑 细胞类型亚组分和认知功能。在Aim 3中，我们探索了宿主基因组在介导 微生物诱导的AD病理学，包括测试SNP与微生物之间的关联，以及 已知AD风险变体/HLA血清型与微生物DNA之间的相互作用来预测AD。这个项目是 重要的是，它可以提供证据表明，预防或治疗感染可以治疗或预防AD。 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测序组织在AD诊断之前收集，并使用仅病例分析来关联 微生物DNA与AD病理学的特定方面。

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.