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) 肽具有抗菌活性，可预防人类疱疹病毒 (HHV)。病毒DNA 在 Aβ 斑块中也可检测到，并且在下一代测序 (NGS) 实验中检测到的 HHV DNA 是 与 AD 风险相关。尽管神经炎症被认为是驱动这种关联的机制， 还有几个问题。最重要的是，尚不清楚感染是否先于 AD 还是衰老的结果 免疫系统或 AD 病理本身。 AD 病理学受感染影响的具体方面是 宿主基因组在调节风险中的作用也是未知的。该项目的目标是回答 通过利用来自血液和大脑样本的 NGS 数据的大型 AD 队列来检测这些问题 微生物 DNA 的存在。在人类 NGS 实验中可以通过以下方式检测和定量微生物 DNA： 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 确定的物种可能是活动性或潜伏性感染的证据。任何有参考价值的微生物 基因组可用，可被检测。这些队列包括阿尔茨海默病测序项目 (ADSP)、阿尔茨海默病神经影像计划 (ADNI)、弗雷明汉心脏研究 (FHS)、 加速药物合作 - 阿尔茨海默病 (AMP-AD) 和光州阿尔茨海默病及相关疾病 痴呆症项目（GARD）。该项目的长期目标是提供证据表明干预措施针对 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 风险并导致 AD 病理学特定方面发生可观察到的变化。我们还假设变异 人类基因组介导这些过程。我们将通过以下具体的测试这些假设 目标。在 Aim1 中，我们将开发一个管道来准确量化和匹配下一步生成的 DNA 片段 对微生物 DNA 序列（包括插入的病毒 DNA）进行世代测序。在 Aim2 中，我们将利用 纵向跟踪具有多组学数据的队列，以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，包括生物标志物、结构 通过磁共振成像测量的大脑变化、神经病理学特征、疾病进展、大脑 细胞类型亚组分和认知功能。在 Aim3 中，我们探讨了宿主基因组在介导中的作用 微生物诱发的 AD 病理学，包括测试 SNP 与微生物之间的关联，以及 已知 AD 风险变异/HLA 血清型和微生物 DNA 之间的相互作用来预测 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 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 测序的组织是在 AD 诊断之前收集的，并使用仅案例分析来链接 微生物 DNA 与 AD 病理学特定方面的关系。

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.