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.

APOE ε4 等位基因是罹患阿尔茨海默病 (AD) 的最强遗传风险因素。 该项目将研究 APOE 基因型对脑脊液 (CSF) DHA 水平和变化的影响 认知健康老年人对 DHA 的结构和功能性大脑连接 DHA 是一种对神经元功能至关重要的必需 omega-3 脂肪酸，并且不是在体内形成的。 足够量的 DHA 在皮质灰质中高度丰富，并且更集中在 在 AD 大脑中，DHA 在突触可塑性中发挥作用的突触被耗尽。 关于 DHA 对认知结果的影响，得出了不同的结果。这项研究提出了一个关键问题： 补充后DHA是否足够量进入大脑，APOE基因型是否 携带人类 APOE ε4 等位基因的小鼠会减少 DHA 的大脑输送。 与表达 APOE ε2 或 APOE ε3 等位基因的小鼠相比，高剂量 DHA 补充剂可以预防。 APOE ɛ4 转基因小鼠模型中的 AD 病理学我们的初步数据表明 DHA 浓度较低。 与非携带者相比，认知健康的 APOE ε4 携带者的 CSF 中存在差异。 携带者减少了 DHA 向脑脊液的输送，这可以在补充高剂量 DHA 后逆转。 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（2 160 名认知健康的参与者按 APOE 状态（ε4 与非 ε4 携带者）的主要结果是 APOE 基因型对 DHA 反应对 CSF DHA 水平的影响。 我们将检查红细胞 DHA 浓度作为外周生物标志物。 我们的次要结果是 24 周的试验，评估大脑结构和功能连接的变化。 静息态功能 MRI 和 APOE ε4 的变化与血脑屏障有关。 分解、低脂化 apoE HDL 和脑淀粉样蛋白沉积 提供对机制的见解。 调节 DHA 大脑输送，我们的第二个目标是检查 CSF DHA 水平变化的关联 在补充血脑屏障完整性的措施（通过脑脊液白蛋白商评估）期间， CSF中apoE颗粒的DHA含量以及CSF Aβ42水平这些研究结果将提供新颖的结果。 可用于临床设计预防高危人群 AD 的个性化方法的信息 鉴于 DHA 的安全性、可用性和可负担性，完善 DHA 对 APOE 的干预。 ε4携带者可以对降低AD发病率产生显着影响。