The Contribution of the Oral Microbiome to Alzheimer’s Disease Risk

摘要 阿尔茨海默病（AD）影响着650万美国人，给我们的社会带来了巨大的负担， 尽管AD在经济上和人类痛苦方面都有很大的改善，但AD的病因学尚未完全了解。AD的危险因素 包括人口统计学、遗传学、生活方式、医学、环境、精神病学和传染病 因素在已知与AD相关的感染因素中，牙周病（PerioD）是其中之一。期间 是牙龈组织的多种微生物感染，是口腔最常见的疾病之一。 人们对PerioD和AD之间的联系越来越感兴趣，但基础疾病之间的机制还不清楚。 这种关联是未知的，大多数研究都集中在有限数量的PerioD上， 相关生物体，例如牙龈卟啉单胞菌（Porphyromonas gingivalis）、牙龈塔内氏菌（Tanerella dentithia）和齿垢密螺旋体（Treponema denticola）。 目前，该领域的一个主要和根本的障碍是缺乏跨界（细菌，病毒，真菌）， PerioD的口腔微生物组的综合表征，因为它与AD风险有关。总的目的 该项目的目的是研究口腔微生物组在风险最高的个体中的临床相关性 对于AD。本纵向队列研究将入组150名中年个体。主要目标是 描述认知正常个体中口腔细菌、病毒和真菌的分类和功能 在为期两年的时间里，研究PerioD相关微生物组之间的关系， 特征、炎症、口腔健康的社会决定因素和AD CSF生物标志物（Aβ42、总Tau和 磷酸-Tau）。我们将利用现有的NIH资助的，特征良好的队列，包括种族多样性， AD高风险个体（通过家族史或APOE 4等位基因）。受试者将完成3次研究访视 每年。将在基线和第2年收集用于AD和炎症标志物的脑脊液。年度 评估和样本采集将包括：临床口腔检查;龈下菌斑， 微生物组评估;唾液炎症标志物;血液全身炎症标志物; 神经心理学测试;和调查（药物/健康史;口腔症状，卫生行为， 生活质量;健康的社会决定因素）。最后，我们将进行半结构化的深度访谈， 探讨口腔健康与AD相关的社会决定因素。生成的数据将通知较大的NIH 资助的研究，并据我们所知，提供最大和最全面的表征的口头 微生物组在一个种族多样化的样本中的个体风险为AD。

Abstract Alzheimer’s disease (AD) affects 6.5 million Americans inflicting tremendous burden on our society both economically and in terms of human suffering, yet the etiology of AD is not fully understood. Risk factors for AD are numerous and include demographic, genetic, lifestyle, medical, environmental, psychiatric, and infectious factors. Among the infectious factors known to be associated with AD is periodontal disease (PerioD). PerioD is a polymicrobial infection of the gingival tissue and one of the most common conditions of the oral cavity. There is a growing interest in the connection between PerioD and AD, yet the mechanism between underlying this association is unknown, and most studies have focused their investigation on a limited number of PerioD- associated organisms, for example Porphyromonas gingivalis, Tanerella forsythia, and Treponema denticola. Currently, a major and fundamental obstacle in the field is the lack of a cross-kingdom (bacterial, viral, fungal), comprehensive characterization of the oral microbiome of PerioD as it relates to AD risk. The overall purpose of the proposed project is to investigate the clinical relevance of the oral microbiome in individuals most at risk for AD. 150 middle aged individuals will be enrolled in this longitudinal cohort study. The main objective is to characterize the taxonomy and function of oral bacteria, viruses and fungi among cognitively normal individuals at risk for AD, and over a two-year period, investigate relationships among PerioD-associated microbiome features, inflammation, social determinants of oral health, and AD CSF biomarkers (Aβ42, total-Tau, and phospho-Tau). We will leverage existing NIH funded, well-characterized cohorts that include racially diverse individuals at high risk for AD (through family history or APOE4 allele). Participants will complete 3 study visits annually. Cerebral spinal fluid for AD and inflammatory markers will be collected at baseline and Yr2. Annual assessments and specimen collection will include: a clinical oral examination; subgingival plaque for microbiome assessment; saliva for inflammatory markers; blood for systemic inflammatory markers; neuropsychological testing; and surveys (medication/health history; oral symptoms, hygiene behavior, and quality of life; social determinants of health). Finally, we will conduct semi-structured in-depth interviews to explore the social determinant factors related to oral health and AD. Generated data will inform larger NIH funded studies and, to our knowledge, provide the largest and most comprehensive characterization of the oral microbiome in a racially diverse sample of individuals at risk for AD.