Implications of metabolism on healthy aging in African and Caucasian Americans: the Health ABC study

阿尔茨海默型(AD)和非AD痴呆症以及神经认知障碍的起源是调节失调的我- 代谢异常，导致痴呆症被认为是“3型糖尿病”的表型。广泛的基础实验室- 以识别精确的代谢缺陷为核心的保守主义、基于模型的系统和人类研究 出现了阿尔茨海默病/非阿尔茨海默病。试图确定新陈代谢基础的研究的一个关键特征 神经认知功能障碍是对表型良好的人进行广泛的新陈代谢评估。 患有痴呆症及相关结果的男性队列。作为R01AG059729的一部分，Shah，Newman，Murthy和 Clish一直在对Healthy Aging and Body Com的一个双细胞亚样本进行代谢物分析- 职位研究(健康ABC)，以确定与健康老龄化相关的代谢途径。当家长学习的时候 包括一些神经认知测量，它只分析Health ABC中的一个子样本的血脂和脂类- 被认为与阿尔茨海默病和相关痴呆相关的关键代谢产物。根据数据显示， 炎症和血脂异常在AD中的重要性正在显现，研究小组要求补充 作为本申请的一部分，完成脂质和脂质中间代谢物概况分析，以促进(1)更广泛的 AD和AD相关表型的科学发现以及(2)已经与其他代谢物模式整合 完成在健康ABC上，提供对生命中重要的代谢异常的更广泛的描述- 神经认知功能障碍和AD的病程。我们假设脂质和脂质介体之间会有关联。 具有AD中心的表型和表型群，并且可能有助于发现潜在的可干预的 阿尔茨海默病和AD相关神经认知功能障碍的核心通路。为了解决这一假设，我们将 在Health ABC的更大样本量中对脂质(C8阳性)和脂质介体进行代谢物分析 (C18阴性)以识别与临床和基于成像的疾病相关的代谢物和编码途径。 TEMA端点。在目标1中，我们将确定与亚基相关的脂质和脂质介体代谢物特征。 顺序认知衰退、临床前AD表型和痴呆症。在目标2中，我们将确定 脂类和脂类介体与选定的痴呆核磁共振标志物先前报道。在目标3中，我们将测试如何 与痴呆症相关的代谢途径因种族和性别以及这些代谢物特征如何相关而有所不同 对于饮食、健身、运动和肥胖，关键的可改变的生活方式特征与改善神经认知功能有关- 提顿。这份副刊的独特之处在于，它是在与Na-A充分合作的情况下构思和构建的。 国立老龄研究所(Luigi Ferrucci博士和曲田博士)，老龄和AD及实质性增强方面的专家 母公司R01授权所涵盖的代谢物分析的样本量，同时利用其实质性的再... 消息来源。完成后将为科学界提供更广泛的定量代谢表型 为了解决AD和AD相关的表型，通过整合Ongo- ING关于衰老的研究，以解决与AD相关的神经认知终点。

Alzheimer-type (AD) and non-AD dementias and neurocognitive impairment have origins in dysregulated me- tabolism, leading to consideration of dementia as a “type 3 diabetes” phenotype. A wide array of basic labora- tory, model systems-based, and human investigations around identifying precise metabolic defects as the core of AD/non-AD dementias have emerged. A critical feature of studies attempting to identify a metabolic basis of neurocognitive dysfunction is the application of a broad assessment of metabolism to a well phenotyped hu- man cohort with dementia and related outcomes. As part of R01AG059729, Drs. Shah, Newman, Murthy and Clish have been performing metabolite profiling in a biracial subsample of the Healthy Aging and Body Com- position Study (Health ABC) to identify metabolic pathways relevant to healthy aging. While the parent study includes some neurocognitive measures, it only assays a subsample within Health ABC for lipid and lipid me- diators, the key metabolites felt to be relevant to AD and related dementias. Based on data suggesting the emerging importance of inflammation and lipid abnormalities in AD, the study team is requesting supplemental funds as part of this application to complete lipid and lipid intermediate metabolite profiling to facilitate (1) wider scientific discovery in AD and AD-related phenotypes and (2) integration with other metabolite modes already completed in Health ABC to provide a wider description of the metabolic abnormalities important in the life- course of neurocognitive dysfunction and AD. We hypothesize that lipid and lipid mediators will be associated with phenotypes and phenotypic groups central to AD and may facilitate discovery of potentially intervenable pathways at the heart of AD and AD-related neurocognitive dysfunction. To address this hypothesis, we will perform metabolite profiling in a wider sample size in Health ABC for lipid (C8 positive) and lipid mediators (C18 negative) to identify metabolites and encoded pathways associated with clinical and imaging-based de- mentia endpoints. In Aim 1, we will identify lipid and lipid mediator metabolite signatures associated with sub- sequent cognitive decline, preclinical AD phenotypes, and dementia. In Aim 2, we will identify association of lipid and lipid mediators with selected MRI markers of dementia previously reported. In Aim 3, we will test how metabolic pathways linked to dementia differ by race and sex and how these metabolite signatures are related to diet, fitness, activity, and adiposity, key modifiable lifestyle features linked to improved neurocognitive func- tion. This supplement is unique in that it has been conceived and constructed in full collaboration with the Na- tional Institutes of Aging (Dr. Luigi Ferrucci and Qu Tian), experts in aging and AD and substantially augments the sample size for metabolite profiling covered by the parent R01 grant, while leveraging its substantial re- sources. Completion would afford the scientific community a wider array of quantitative metabolic phenotyping to address AD and AD-related phenotypes, directly addressing NOT-AG-20-008 by integrating efforts in ongo- ing studies of aging to address neurocognitive endpoints relevant to AD.