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

预防阿尔茨海默病的精准营养：饮食模式、肠道微生物组和认知功能的前瞻性研究

• 批准号: 10629237
• 负责人: Dong Wang
• 金额: $ 87.81万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629237
• 关键词: Acids; Address; Adherence; Adult; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Amyloid beta-42; Animal Model; Bifidobacterium; Bile Acids; Bioinformatics; Biological Markers; Biometry; Brain-Derived Neurotrophic Factor; Branched-Chain Amino Acids; Butyrates; Cognition; Cognitive; Cohort Studies; Data; Dementia; Deoxycholic Acid; Diet; Dietary Assessment; Dietary Intervention; Dietary Practices; Enzymes; Epidemiology; Flavonoids; Genetic Transcription; Glial Fibrillary Acidic Protein; Health; Human; Human Microbiome; Impaired cognition; Individual; Individual Differences; Intervention; Knowledge; Kynurenine; Lactobacillus; Light; Link; Magnetic Resonance Imaging; Measures; Mediating; Mediterranean Diet; Metabolic; Metabolism; Metagenomics; Microbial Taxonomy; Molecular; Nerve Degeneration; Neurology; Neurotransmitters; Nurses' Health Study; Outcome Assessment; Participant; Peptides; Plasma; Population; Positioning Attribute; Prevention; Production; Prospective Studies; Randomized; Reporting; Reproducibility; Research; Research Design; Research Priority; Resolution; Resources; Risk; Role; Sampling; Shotguns; Taxonomy; Technology; Time; Volatile Fatty Acids; abeta accumulation; adjudication; aged; blood-brain barrier permeabilization; brain magnetic resonance imaging; cognitive function; cost efficient; design; dietary; dietary approach; follow-up; gamma-Aminobutyric Acid; gut microbiome; gut microbiota; high risk; improved; indexing; individual variation; individualized prevention; insight; metabolomics; metatranscriptomics; microbial; microbial composition; microbiome; mild cognitive impairment; molecular phenotype; neurofilament; neuroinflammation; novel; novel marker; nutrition; personalized approach; precision medicine; precision nutrition; predictive marker; randomized trial; response; systemic inflammatory response; trimethyloxamine

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.

项目概要 该提案直接涉及一个高度优先的研究主题，“为患者提供精准医疗” 通过深度分子表型分析阿尔茨海默病和相关痴呆症”，PAR-19-070，研究 通过开始开发精准饮食，关注阿尔茨海默病及其相关痴呆症的当前主题 通过整合多种分子数据类型来预防 AD 的方法。健康的潜力 维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， 这些健康的饮食模式是根据人口平均水平制定的，可能并不最适合 给定个人。我们小组和其他人的初步数据支持研究个性化的基本原理 针对个体肠道微生物群量身定制的方法，以改善阿尔茨海默氏痴呆症 (AD) 的饮食预防。 然而，尚无研究探讨肠道微生物组在饮食认知中的改变和调节作用。 协会。对 AD 肠道微生物组的少数人体研究受到小尺寸、横截面的限制。 设计，并且缺乏高分辨率的微生物功能分析。这个背景支撑着我们的中央 假设 1) 健康的饮食模式部分通过调节肠道来促进认知健康 微生物组； 2）饮食模式与认知功能的关联因个体肠道微生物而异 配置文件。该提案代表了一项利用现有粪便的极具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 研究设计、饮食和结果评估：护士健康研究 II (NHSII，n =1,500) 经过数十年的反复饮食评估和长期随访，地中海 DASH 干预措施 神经退行性延迟 (MIND) 随机饮食干预试验 (n =604) 和 ASPREE-XT 研究 (n = 13,000) 已裁定事件 AD 终点。为了获得更先进的机制见解，我们 将采用多组学方法结合鸟枪法宏基因组学和宏转录组学来分析 微生物组成和酶功能，以及粪便代谢组学来测量微生物组代谢 活动。我们将研究肠道微生物组成和酶功能在 地中海饮食（MedDiet）和具有认知功能的 MIND 饮食（目标 1）并检查 两种健康饮食模式、肠道微生物组的代谢活动和 NHSII 中的认知功能（目标 2）。我们将在 ASPREE-XT 和 ASPREE-XT 中复制目标 1 和 2 的发现 MIND 审判（目标 3）。该项目将产生有关肠道微生物和粪便的可重复的转化证据 代谢组学特征解释了个体间异质性对健康饮食模式的反应和 提供基础知识，以最大限度地发挥饮食方法的好处，发现新的预测方法 生物标志物，最终有助于精准预防 AD。