Towards Precision Nutrition for Alzheimer's Dementia Prevention: A Prospective Study of Dietary Patterns, the Gut Microbiome and Cognitive Function

项目总结 这项提议直接涉及一个高优先级的研究主题，即为 阿尔茨海默病和相关痴呆通过深分子表型鉴定“，为PAR-19-070，研究 关于阿尔茨海默病及其相关痴呆症的当前话题--开始开发精确饮食 通过整合多种分子数据类型预防AD的方法。健康的潜力 保持认知健康的饮食模式得到了队列研究和随机试验的支持。然而， 这些健康饮食模式是根据人口平均水平制定的，可能并不是最适合 给定的个人。来自我们团队和其他人的初步数据支持个性化研究的基本原理 针对个别肠道微生物群量身定做的方法，以改善阿尔茨海默氏病(AD)的饮食预防。 然而，还没有研究检查肠道微生物群在饮食认知中的修饰和中介作用。 协会。为数不多的关于阿尔茨海默病患者肠道微生物组的人类研究受到规模小、横截面的限制 缺乏高分辨率的微生物功能图谱。这一背景支持我们的中央 假设1)健康的饮食模式有助于认知健康，部分是通过调节肠道 2)饮食模式与认知功能的关联因个体肠道微生物的不同而不同 配置文件。这项建议代表了一项利用现有排泄物进行的高成本效益的前瞻性研究 三项优势互补的研究中的样本/微生物组数据和认知功能评估 在研究设计、饮食和结果评估方面：护士健康研究II(NHSII，n=1,500) 长达数十年的重复饮食评估和延长的随访，地中海-DASH干预 神经退行性延迟(Mind)随机饮食干预试验(n=604)，以及ASPREE-XT 研究(n=13,000)，包括已判定的事件AD终点。为了获得更先进的机械论见解，我们 将采取多组学的方法结合鸟枪式元基因组学和元翻译组学来描述 微生物组成和酶功能，以及粪便代谢组学测量微生物组代谢 活动。我们将研究肠道微生物组成和酶功能在肠道疾病相关性中的作用。 地中海饮食(MedDiet)和具有认知功能的心灵饮食(目标1)，并检查 两种健康饮食模式之间的相互关系，肠道微生物组的代谢活动和 NHSII的认知功能(目标2)。我们将在ASPREE-XT和ASPREE-XT中复制AIMS 1和2的研究结果 心理测试(目标3)。这个项目将产生关于肠道微生物和粪便的可复制的、可翻译的证据 代谢组学特征，解释个体间的异质性对健康饮食模式和 为最大限度地发挥饮食方法的优势提供基础知识，发现新的预测性 生物标志物，并最终有助于AD的精确预防。

PROJECT SUMMARY This proposal directly addresses a high-priority research topic, “Enabling precision medicine for Alzheimer’s disease and related dementias through deep molecular phenotyping”, for PAR-19-070, Research on Current Topics in Alzheimer's Disease and Its Related Dementias, by beginning to develop precision dietary approaches for AD prevention through integrating multiple molecular data types. The potential for healthy dietary patterns to maintain cognitive health is supported by cohort studies and a randomized trial. However, these healthy dietary patterns were developed based on population averages and may not be best suited for a given individual. Preliminary data from our group and others support the rationale to study personalized approaches tailored to individual gut microbiomes to improve dietary prevention of Alzheimer’s dementia (AD). However, no study has examined modifying and mediating roles of the gut microbiome in the diet-cognition association. The few human studies of the gut microbiome in AD were limited by small size, cross-sectional design, and lack of high-resolution microbial functional profiling. This background supports our central hypotheses that 1) healthy dietary patterns contribute to cognitive health partly through modulating the gut microbiome; and 2) associations of the dietary patterns with cognitive function vary by individuals’ gut microbial profiles. This proposal represents a highly cost-efficient, prospective study leveraging existing fecal samples/microbiome data and cognitive function assessments in three studies with complementary strengths in study design, and diet and outcome assessments: the Nurses’ Health Study II (NHSII, n =1,500) with decades-long repeated dietary assessments and extended follow-up, the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) Trial with randomized dietary interventions (n =604), and the ASPREE-XT Study (n =13,000) with adjudicated incident AD endpoints. To gain more advanced mechanistic insights, we will take a multi’omic approach to combine shotgun metagenomics and metatranscriptomics to profile the microbial composition and enzymatic function, and fecal metabolomics to measure the microbiome metabolic activity. We will investigate roles of gut microbial composition and enzymatic function in the associations of the Mediterranean diet (MedDiet) and the MIND Diet with cognitive function (Aim 1) and examine the interrelationships among the two healthy dietary patterns, the metabolic activity of the gut microbiome and cognitive function (Aim 2) in the NHSII. We will replicate findings from Aims 1 and 2 in ASPREE-XT and the MIND Trial (Aim 3). This project will generate reproducible, translational evidence on gut microbial and fecal metabolomic features that explain inter-individual heterogeneity in response to healthy dietary patterns and provide foundational knowledge for maximizing the benefits of dietary approaches, discovering novel predictive biomarkers, and ultimately contributing to precision prevention of AD.