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

项目总结 慢性全身性炎症是认知功能减退和阿尔茨海默病(AD)的重要因素 以及老年人的阿尔茨海默病相关痴呆(ADRD)。大规模的基因研究已经 更有力的证据表明，炎症基因在导致神经炎症的神经性炎症中发挥主要作用 神经退行性变和认知丧失。膳食omega-3(n-3)和omega-6(n-6)多不饱和脂肪酸 (从鱼、坚果、种子和某些油中提取)可以抗炎。然而，抗炎和抗炎的证据 即使在随机的、受控的干预中，对饮食脂肪酸的认知保护也是复杂的。遗传 影响全身炎症的变种可能导致n-3和n-6之间不一致的关联 脂肪酸和认知功能。为了研究这一假设，我们将进行全基因组范围的相互作用 亚油酸(18：2，n-6)、花生四烯酸(20：4，n-6)、α-亚麻酸常见变种的分析 (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) 多民族人群(西班牙裔和非洲裔)的C反应蛋白和白介素6的检测 美国人、中国人和欧洲人的血统)，并将它们结合起来进行元分析。接下来，我们将进行类似的 与相同的五种n-3和n-6脂肪酸以及低频率/稀有遗传变异的相互作用分析， 可能会产生更大的影响大小。我们通过预测的相互作用分析确定的遗传变异 为了对每种脂肪酸做出反应，然后将CRP和IL-6结合起来，生成一个多基因风险分数 评估与1)偶发性痴呆和2)协调的总体认知功能评分的相关性 CHARD(基因组流行病学中心脏和衰老研究的队列)队列的子集 认知结果。我们设计的几个方面增加了它的严谨性。首先，电荷分布在 美国、欧洲和亚洲，并提供了一个关键的多种族平台，以确定遗传来源的变异 对脂肪酸的反应。多国家、多种族的方面是必不可少的，因为脂肪酸组成、饮食 模式和遗传结构因种族和全球不同而不同。第二，参与的队列有 已经测量了血液中的一组单独的常见脂肪酸，提供了一个客观的评估 膳食摄入量和内源性代谢的生物标志物。这种基于血液的脂肪酸测量是有价值的， 因为它提供了必需饮食脂肪酸的精确测量，以改善基因与饮食的相互作用 发现号。这项研究将提供关键证据，说明五种常见的饮食脂肪酸如何改善 全身性炎性生物标记物降低痴呆的遗传风险。来自多个队列的研究结果， 跨学科项目将为多地点饮食干预的设计提供信息，以减少系统性 炎症，预防或延缓AD和ADRD。

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.