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

载脂蛋白E ε4等位基因是阿尔茨海默病（Alzheimer's disease，AD）最强的遗传危险因子。拟议 该项目将研究载脂蛋白E基因型对脑脊液（CSF）DHA水平和 DHA对认知健康老年人大脑结构和功能连接的影响 补充。DHA是一种对神经元功能至关重要的必需ω-3脂肪酸， 足够的量从头开始。DHA在皮质灰质中高度富集， 在突触可塑性中发挥作用。DHA在AD大脑中被耗尽。随机临床试验 在DHA对认知结果的影响方面取得了不同的结果。这项研究提出了一个关键问题， 补充后DHA是否能足量进入大脑，以及APOE基因型 影响大脑的恍惚状态携带人类APOE ε4等位基因的小鼠大脑中DHA的释放减少 与表达APOE ε2或APOE ε3等位基因的小鼠相比。高剂量DHA补充剂可预防 APOE β 4转基因小鼠模型中的AD病理学。我们的初步数据表明， 在认知健康的APOE ε4携带者与非携带者的CSF中。我们假设APOE ε4 载体减少了DHA向CSF的递送，这可以在高剂量DHA补充后逆转。 为了解决这一假设，我们提出了一个双盲安慰剂对照的临床试验，高剂量（2 在160名认知健康的参与者中，根据APOE状态（ε4与非ε 4）分层， ε4载体）。主要结果是APOE基因型对DHA引起的CSF DHA水平的影响 补充。我们将检查红细胞DHA浓度作为外周生物标志物， 24-周审判我们的次要结果是大脑结构和功能连接的变化， 静息状态功能性MRI和认知变化。APOE ε4与血脑屏障相关 分解、低脂化apoE HDL和脑淀粉样蛋白沉积。深入了解 调节DHA的大脑传递，我们的第二个目的是检查脑脊液DHA水平的变化与 在补充测量血脑屏障完整性（通过CSF白蛋白商评估）期间， CSF中apoE颗粒的DHA含量和CSF Aβ42水平。这些研究结果将提供新的 这些信息可用于临床设计个性化的方法，以预防高风险人群中的AD。 个体考虑到DHA的安全性、可用性和可负担性， ε4携带者对降低AD发病率具有显著影响。

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.