The delivery of essential fatty acids to the Brain in Alzheimer's disease

向阿尔茨海默病患者的大脑输送必需脂肪酸

• 批准号: 9924424
• 负责人: Hussein N Yassine
• 金额: $ 88.43万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924424
• 关键词: Abeta clearance; Address; Affect; Age; Albumins; Alleles; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Amyloid beta-42; Amyloid deposition; Apolipoprotein E; Biological Markers; Biometry; Blood - brain barrier anatomy; Brain; Brain imaging; Cerebrospinal Fluid; Clinical; Clinical Trials; Cognition; Cognitive; Collaborations; Controlled Clinical Trials; Data; Defect; Dementia; Disease; Docosahexaenoic Acids; Docosahexaenoic acid supplementation; Dose; Double-Blind Method; Erythrocytes; Essential Fatty Acids; Functional Magnetic Resonance Imaging; Genotype; Goals; High Density Lipoproteins; Human; Impaired cognition; Incidence; Individual; Intervention; Laws; Lipoproteins; Maintenance; Measures; Membrane; Metabolism; Mus; Neurons; Nutrient; Omega-3 Fatty Acids; Outcome; Participant; Penetrance; Peripheral; Persons; Phase III Clinical Trials; Phospholipase A2; Placebos; Plasma; Play; Population; Production; Public Health; Randomized; Randomized Clinical Trials; Reporting; Research; Rest; Risk; Rodent; Role; Safety; Structure; Supplementation; Synapses; Synaptic plasticity; Target Populations; Transgenic Mice; apolipoprotein E-4; cognitive change; cost effective; design; effective therapy; genetic risk factor; gray matter; high risk; insight; mouse model; non-demented; novel; particle; personalized approach; prevent; primary outcome; programs; response; secondary outcome; therapy development; week trial

APOE ε4 allele is the strongest genetic risk factor for developing Alzheimer's disease (AD). The proposed project will examine the effect of APOE genotype on cerebrospinal fluid (CSF) DHA levels and on changes in structural and functional brain connectivity in cognitively healthy older individuals in response to DHA supplementation. DHA is an essential omega-3 fatty acid critical to neuronal functions, and is not formed in sufficient amounts de novo. DHA is highly enriched in cortical grey matter and is more concentrated at synapses where it plays a role in synaptic plasticity. DHA is depleted in AD brains. Randomized clinical trials have yielded mixed results on the effect DHA on cognitive outcomes. This study asks the critical question of whether DHA gets into the brain in sufficient amounts after supplementation, and whether APOE genotype affects brain penetrance. Mice carrying the human APOE ε4 allele have decreased brain delivery of DHA compared to mice expressing the APOE ε2 or the APOE ε3 allele. High dose DHA supplementation prevents AD pathology in APOE ɛ4 transgenic mouse models. Our preliminary data indicate lower DHA concentrations in the CSF of cognitively healthy APOE ε4 carriers compared to non-carriers. We hypothesize that APOE ε4 carriers have reduced delivery of DHA to the CSF that can be reversed upon high dose DHA supplementation. To address this hypothesis, we propose a double-blind placebo-controlled clinical trial of high dose (2 grams/day) of DHA over 6 months in 160 cognitively healthy participants stratified by APOE status (ε4 vs. non ε4 carriers). The primary outcome is the effect of APOE genotype on CSF DHA levels in response to DHA supplementation. We will examine red blood cell DHA concentrations as a peripheral biomarker following the 24-week trial. Our secondary outcomes are changes in brain structural and functional connectivity assessed by resting state functional MRI, and changes in cognition. APOE ε4 is associated with blood-brain barrier breakdown, hypolipidated apoE HDL, and brain amyloid deposition. To provide insights into mechanisms regulating DHA brain delivery, our second aim is to examine the association of the change in CSF DHA levels during supplementation with measures of blood-brain barrier integrity (assessed by the CSF albumin quotient), DHA content of apoE particles in CSF, and CSF Aβ42 levels. The results of these studies will provide novel information that can be used clinically to design personalized approaches for the prevention of AD in high-risk individuals. Given the safety profile, availability, and affordability of DHA, refining a DHA intervention in APOE ε4 carriers can have significant impact on reducing AD incidence.

APOEε4等位基因是发展阿尔茨海默氏病（AD）的强大遗传危险因素。提议 项目将检查APOE基因型对脑脊液（CSF）DHA水平的影响以及对变化的变化 响应DHA的认知健康老年人的结构和功能性大脑连通性 补充。 DHA是至关重要的omega-3脂肪酸，对神经元功能至关重要，在 从头开始足够。 DHA在皮质灰质中高度富集，并且更集中在 突触在突触可塑性中起作用。 DHA在广告大脑中耗尽。随机临床试验 对DHA对认知结果的影响产生了不同的结果。这项研究提出了一个关键问题 补充后DHA是否以足够的量进入大脑，以及APOE基因型是否 影响大脑的渗透。携带人ApoEε4等位基因的小鼠的大脑递送改善了DHA 与表达APOEε2或APOEε3等位基因的小鼠相比。高剂量DHA补充可防止 APOEɛ4转基因小鼠模型中的AD病理。我们的初步数据表明DHA浓度较低 与非载体相比，在认知健康的APOEε4载体的CSF中。我们假设APOEε4 载体减少了DHA向CSF的递送，在补充高剂量DHA时可以逆转。 为了解决这一假设，我们提出了一项高剂量的双盲安慰剂对照临床试验（2 DHA在6个月内的克/天）在160个认知健康的参与者中按APOE状态分层（ε4vs.非 ε4载体）。主要结果是APOE基因型对DHA的CSF DHA水平的影响 补充。我们将检查红细胞DHA浓度作为外围生物标志物 24周试验。我们的次要结果是由大脑结构和功能连通性的变化。 静止状态功能MRI和认知变化。 Apoeε4与血脑屏障有关 崩溃，低脂化的APOE HDL和脑淀粉样蛋白沉积。提供有关机制的见解 调节DHA脑输送，我们的第二个目的是检查CSF DHA水平变化的关联 在补充血脑屏障完整性（由CSF白蛋白评估）的衡量标准期间， CSF中APOE颗粒的DHA含量和CSFAβ42水平。这些研究的结果将提供新颖 可以在临床上用于设计个性化方法以预防高风险的信息 个人。鉴于DHA的安全性，可用性和可用性，请在APOE中进行DHA干预 ε4载体可能会对减少AD事件产生重大影响。