Impact of Icosapent Ethyl on Alzheimers Disease Biomarkers in Preclinical Adults

 描述（由申请人提供）： 超过500万美国人患有阿尔茨海默病（AD），除非找到有效的预防策略，否则预计到2050年这一数字将增加两倍。退伍军人患AD的风险甚至高于普通人群，这可能是由于他们更多地暴露于加速AD病理的因素，包括血管风险因素，创伤性脑损伤和创伤后应激障碍。AD病理学在认知症状发生前几十年发生，其特征在于淀粉样蛋白斑块、神经元缠结和与记忆和学习相关的大脑区域中的局部脑血流量减少。虽然脑动脉功能障碍发生在AD病理学发展的早期，并且在症状开始之前几十年，但对治疗这种早期脑血管功能障碍的效果知之甚少。ω-3脂肪酸二十碳五烯酸（EPA）可改善动脉功能和脑血流量，减弱与β-淀粉样蛋白相关的不良大脑变化，并改善动物的认知-这些变化都可能预防AD。然而，目前尚不清楚EPA是否有益于AD风险增加的认知健康成年人的这些过程或认知表现。2012年，美国食品和药物管理局批准了第一种仅含EPA的高剂量处方药来治疗高脂血症，称为二十碳五烯酸乙酯（在美国以Vascepa（r）的形式提供）。这种药物易于使用，具有良好的安全性，使其成为预防AD的有利药物。拟定的研究是一项概念验证、随机、安慰剂对照、双盲、平行组临床试验，评估了18个月的二十碳五烯酸乙酯治疗对磁共振成像（MRI）、脑脊液（CSF）、和AD的认知生物标志物在150名认知健康的退伍军人年龄50- 70例患者由于父母的疾病史和载脂蛋白E ε4（APOE 4）等位基因的患病率增加而导致AD的风险增加。本试验的总体目标是评估二十碳五烯酸乙酯是否有益地影响与AD发作相关的中间生理指标，以评估是否有必要进行更大规模、多中心、持续时间更长的阿尔茨海默病预防试验，以评估更明确的临床结局。假设：在父母有AD病史且APOE 4患病率较高的中老年认知健康退伍军人中，使用二十碳五烯酸乙酯治疗18个月将有益地改变临床前AD生物标志物，包括局部脑血流量、AD病理学的CSF标志物和认知表现。具体目标1：研究18个月的二十碳五烯酸乙酯4 g每日一次与安慰剂相比对临床前AD早期受影响的预定义的经病理学鉴定的感兴趣区域中动脉自旋标记MRI局部脑血流量的影响;具体目的2：确定18个月二十碳五烯酸乙酯与安慰剂相比对临床前AD病理学CSF生物标志物的影响（CSF β-淀粉样蛋白-42、总tau蛋白和磷酸化tau蛋白181）;具体目标3：评价18个月的二十碳五烯酸乙酯与安慰剂相比对旨在评估临床前认知变化的复合指标的影响-阿尔茨海默病合作研究（ADCS）临床前阿尔茨海默氏认知复合指标（PACC）。如果二十碳五烯酸乙酯有益地改变了处于风险中的退伍军人的AD生物标志物，则拟议试验的结果将用于使用VA合作研究计划开发多中心，持续时间更长的临床试验，以评估二十碳五烯酸乙酯不仅对AD生物标志物的疗效，而且对临床上更明确的结果，如认知下降率和转化为轻度认知障碍（MCI）。如果未来的研究表明，二十碳五烯酸乙酯可以将AD的发病时间平均推迟5年，估计这可能会使AD的患病率降低约50%。

 DESCRIPTION (provided by applicant): Over five million Americans have Alzheimer's disease (AD), and this number is expected to triple by 2050 unless effective preventive strategies are identified. Veterans are at an even higher risk for AD than the general population, possibly due to their increased exposure to factors that accelerate AD pathology, including vascular risk factors, traumatic brain injury, and post-traumatic stress disorder. AD pathology occurs decades before cognitive symptoms occur and is characterized by amyloid plaques, neurofibrillary tangles, and reduced regional cerebral blood flow in areas of the brain related to memory and learning. While cerebral arterial dysfunction occurs early in the development of AD pathology and decades before symptoms begin, the effects of treating such early vascular dysfunction in the brain are poorly understood. The omega-3 fatty acid eicosapentaenoic acid (EPA) improves arterial function and cerebral blood flow, attenuates adverse brain changes related to β-amyloid protein, and improves cognition in animals - changes that could all potentially protect against AD. However, it is not clear whether EPA beneficially affects these processes or cognitive performance in cognitively-healthy adults at increased risk for AD. In 2012, the Food and Drug Administration approved the first high-dose prescription EPA-only medication to treat hypertriglyceridemia, called icosapent ethyl (available as Vascepa(r) in the United States). This agent is readily available for use and has a good safety profile, making it a favorable agent to consider for AD prevention. The proposed study is a proof-of-concept, randomized, placebo-controlled, double-blind, parallel-group clinical trial assessing the efficacy of 18 months of icosapent ethyl therapy on magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and cognitive biomarkers for AD in 150 cognitively-healthy Veterans ages 50-70 with increased risk for developing AD due to parental history of the disease and increased prevalence of apolipoprotein E ε4 (APOE4) allele. The overarching goal of this trial is to assess whether icosapent ethyl beneficially affects intermediate physiological measures associated with onset of AD in order to evaluate whether larger, multi-site, longer-duration Alzheimer's prevention trials are warranted to assess more definitive clinical outcomes. Hypothesis: In middle-aged and older cognitively-healthy Veterans with parental history of AD and high APOE4 prevalence, 18 months of treatment with icosapent ethyl will beneficially modify preclinical AD biomarkers, including regional cerebral blood flow, CSF markers of AD pathology, and cognitive performance. Specific Aim 1: To investigate the effects of 18 months of icosapent ethyl 4 g daily vs. placebo on arterial spin-labeling MRI regional cerebral blood flow in a pre-defined statistically-identified region of interest affected early in preclinical AD; Specific Aim 2: To determine the impact of 18 months of icosapent ethyl vs. placebo on CSF biomarkers of preclinical AD pathology (CSF β-amyloid- 42, total tau, and phosphorylated tau181); Specific Aim 3: To evaluate the effects of 18 months of icosapent ethyl vs. placebo on a composite measure designed to assess preclinical cognitive changes - the Alzheimer's Disease Cooperative Study (ADCS) Preclinical Alzheimer's Cognitive Composite (PACC). If icosapent ethyl beneficially modifies AD biomarkers in at-risk Veterans, the results from the proposed trial would be used to develop multi-site, longer-duration clinical trials using the VA Cooperative Studies Program to assess the efficacy of icosapent ethyl on not only AD biomarkers, but also on more clinically definitive outcomes, such as rate of cognitive decline and conversion to mild cognitive impairment (MCI). If future studies show that icosapent ethyl delays the onset of AD by even an average of 5 years, estimates suggest that this could reduce the prevalence of AD by about 50%.