Circulating fatty acids, genetics of inflammation and AD-related dementia and cognitive decline

循环脂肪酸、炎症遗传学以及 AD 相关痴呆和认知能力下降

基本信息

批准号：
10230534
负责人：
Caren Elizabeth Smith
金额：
$ 33.73万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10230534
关键词：
Address Affect African American Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Anti-Inflammatory Agents Arachidonic Acids Asia Biological Markers Biomarker of Dietary Intake Blood Brain C-reactive protein Charge Chinese People Chronic Cognitive Complex Dementia Diet Dietary Essential Fatty Acid Dietary Fatty Acid Dietary Intervention Dietary Practices Docosahexaenoic Acids Effectiveness Eicosapentaenoic Acid Elderly Epidemiology Ethnic Origin Europe European Evaluation Family Fatty Acids Fishes Food Frequencies Future G-Protein-Coupled Receptors Genes Genetic Genetic Risk Genetic study Health Heart Hispanic Americans Impaired cognition Individual Inflammation Inflammatory Inflammatory Response Intake Interleukin-6 Intervention Level of Evidence Ligands Link Linoleic Acids Measurement Measures Mediating Mediator of activation protein Medical Meta-Analysis Metabolism Nerve Degeneration Neurocognitive Deficit Neurons Nuts Oils Omega-3 Fatty Acids Omega-6 Fatty Acids Outcome Patient Self-Report Play Polygenic Traits Polyunsaturated Fatty Acids Population Population Heterogeneity Prevention Public Health Questionnaires Randomized Research Risk Role Seeds Site Source Testing Translations Variant Work age related alpha-Linolenic Acid apolipoprotein E-4 base cognitive function cohort design genetic architecture genetic variant genome-wide genome-wide analysis genomic epidemiology improved neuroinflammation neuroprotection novel polygenic risk score prevent rare variant response stem

项目摘要

PROJECT SUMMARY Chronic, systemic inflammation is an established mediator of cognitive decline and Alzheimer’s disease (AD) and Alzheimer’s disease-related dementias (ADRD) in older adults. Large-scale genetic studies have strengthened evidence that inflammatory genes play a major role in neuroinflammation that leads to neurodegeneration and cognitive loss. Dietary omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (from fish, nuts, seeds, and certain oils) can be anti-inflammatory. However, evidence of anti-inflammatory and cognitive protection from dietary fatty acids is mixed, even in randomized, controlled interventions. Genetic variants that affect systemic inflammation likely contribute to inconsistent associations between n-3 and n-6 fatty acids and cognitive function. To investigate this hypothesis, we will conduct genome-wide interaction analyses of common variants with linoleic acid (18:2, n-6), arachidonic acid (20:4, n-6), alpha-linolenic acid (18:3, n-3), eicosapentaenoic acid (20:5, n-3), docosahexaenoic acid (22:6, n-3) for the outcomes of high- sensitivity C reactive protein (CRP) and interleukin 6 (IL-6) in multi-ethnic cohorts (Hispanic and African Americans, Chinese and European descent) and combine them meta-analytically. Next, we will conduct similar interaction analyses with the same five n-3 and n-6 fatty acids and low frequency/rare genetic variants, which are likely to be of larger effect size. Genetic variants that we identity though interaction analyses as predicted to respond to each fatty acid for CRP and IL-6 will then be combined to generate a polygenic risk score for evaluation of association with 1) incident dementia and 2) a harmonized overall cognitive function score in a subset of CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) cohorts with robust cognitive outcomes. Several aspects of our design increase its rigor. First, CHARGE populations are located in the US, Europe and Asia and provide a critical multi-ethnic platform to identify genetic sources of variability in response to fatty acids. The multi-national, multi-ethnic aspect is essential because fatty acids profiles, dietary patterns and genetic architecture differ by ethnicity and across the globe. Second, participating cohorts have already measured a panel of individual, common fatty acids in the blood, providing an objectively assessed biomarker of dietary intake and endogenous metabolism. This blood-based fatty acid measurement is valuable, because it provides a precise measurement of essential dietary fatty acids, to improve gene-diet interaction discovery. This research will provide critical evidence of how five common dietary fatty acids ameliorate the genetic risk of systemic inflammatory biomarkers to reduce dementia. Findings from this multi-cohort, interdisciplinary project will inform the design of multi-site dietary interventions to reduce systemic inflammation, to prevent or delay AD and ADRD.

项目概要慢性全身炎症是认知能力下降和阿尔茨海默病 (AD) 的既定介质以及老年人中与阿尔茨海默病相关的痴呆症（ADRD）。更有证据表明炎症基因在导致神经炎症的过程中发挥着重要作用饮食中的 omega-3 (n-3) 和 omega-6 (n-6) 多不饱和脂肪酸。（来自鱼、坚果、种子和某些油）可以具有抗炎作用，但有证据表明其具有抗炎作用。膳食脂肪酸对认知的保护作用是混合的，即使是在随机、受控的遗传干预中也是如此。影响全身炎症的变异可能导致 n-3 和 n-6 之间的关联不一致为了研究这一假设，我们将进行全基因组相互作用。亚油酸 (18:2, n-6)、花生四烯酸 (20:4, n-6)、α-亚麻酸的常见变体分析 (18:3, n-3)、二十碳五烯酸 (20:5, n-3)、二十二碳六烯酸 (22:6, n-3) 多种族群体（西班牙裔和非洲裔）中 C 反应蛋白 (CRP) 和白细胞介素 6 (IL-6) 的敏感性美国人、中国人和欧洲人血统）并将它们结合起来进行元分析接下来，我们将进行类似的操作。与相同的五种 n-3 和 n-6 脂肪酸以及低频/稀有遗传变异体的相互作用分析，正如预测的那样，我们通过相互作用分析识别出的遗传变异可能具有更大的效应量。然后将对 CRP 和 IL-6 的每种脂肪酸做出反应，然后将其组合起来生成多基因风险评分与 1) 痴呆症和 2) 协调整体认知功能评分相关的事件评估 CHARGE（基因组流行病学心脏和衰老研究队列）队列的子集，具有强大的我们设计的几个方面提高了其严谨性，首先，CHARGE 人群位于。美国、欧洲和亚洲，并提供一个重要的多种族平台来识别变异的遗传来源对脂肪酸的反应至关重要，因为脂肪酸谱、饮食结构。其次，参与群体的模式和遗传结构因种族和全球范围的不同而不同。已经测量了血液中一组单独的常见脂肪酸，提供了客观的评估这种基于血液的脂肪酸测量是有价值的，因为它可以精确测量必需膳食脂肪酸，以改善基因与饮食的相互作用这项研究将为五种常见膳食脂肪酸如何改善健康提供重要证据。全身炎症生物标志物的遗传风险可减少痴呆症。跨学科项目将为多部位饮食干预的设计提供信息，以减少系统性饮食炎症，预防或延缓 AD 和 ADRD。