Effects of Simvastatin on CSF AD biomarkers in cognitively normal subjects

描述（由申请人提供）：阿尔茨海默病（AD）的一级预防有望带来巨大的临床和经济效益，但也面临着巨大的挑战，因为AD的病理过程比痴呆的临床症状早几年甚至几十年。使用脑脊液（CSF） AD生物标志物（例如，总tau [t-tau]，苏氨酸181磷酸化的tau [p-tau181]和A¿42）作为临床试验终点，在合理的样本量和随访期间的设计中，有可能证明假定的预防药物的疾病修饰作用。辛伐他汀是一种安全且广泛使用的降胆固醇药物，是一种有吸引力的候选预防药物，来自我们实验室和其他实验室的流行病学研究表明，他汀类药物的使用与降低临床AD风险和减少尸检时神经原纤维缠结负担有关。此外，我们最近证明，在认知正常的高胆固醇血症患者中，接受14周辛伐他汀（具有较高的中枢神经系统穿透性）治疗可降低脑脊液中t-tau和p-tau181的水平，而普伐他汀（具有较低的中枢神经系统穿透性）治疗则无此效果。该试点研究提供了有价值的“概念验证”证据，证明使用CSF AD生物标志物作为临床试验终点既安全又可行。本研究是一项为期1年的固定剂量、随机、安慰剂对照试验，以评估辛伐他汀（40mg /d）与安慰剂对中年（45-64岁）认知正常受试者脑脊液AD生物标志物的影响（每组N=50）。主要预后指标为脑脊液t-tau、p-tau181、A¿42和脑源性神经营养因子（BDNF）。次要结局指标包括炎症标志物（白介素[IL]-6、IL-8、S1002）、氧化应激标志物（f2 -异前列腺素）和脑胆固醇代谢物（24s -羟基胆固醇）。研究结果和认知安全评估（简单和持续注意力、工作和陈述性记忆以及复杂推理的心理测量）将在治疗前和治疗12个月时进行测量。不良反应（包括血脂、肝功能检查和肌酸磷酸激酶水平）将在6周和3、6、12个月时监测。拟议研究的结果可能为在AD高危人群中进行大规模一级预防试验提供支持，该试验使用CSF生物标志物作为主要结局指标。公共卫生相关性：阿尔茨海默病（AD）的一级预防既能为患者及其家庭带来临床效益，也能为社会带来可观的经济效益。将阿尔茨海默病的发病推迟5年，将在一代人的时间内使阿尔茨海默病病例数量减少50%，从而节省数十亿美元的医疗费用。辛伐他汀已被广泛用于预防冠状动脉疾病。拟议研究的结果可能为支持在AD高危人群中进行大规模一级预防试验提供概念证明。

DESCRIPTION (provided by applicant): Primary prevention of Alzheimer's disease (AD) promises great clinical and economic benefits but poses great challenges because the pathologic processes of AD start years or even decades prior to clinical symptoms of dementia. Using cerebrospinal fluid (CSF) AD biomarkers (e.g., total tau [t-tau], tau phosphorylated at threonine 181 [p-tau181] and A¿42) as clinical trial endpoints offers the potential to demonstrate disease- modifying effects of putative preventive agents in designs with reasonable sample sizes and follow up periods. Simvastatin, a safe and widely used cholesterol-lowering drug, is an attractive candidate preventive agent, as epidemiologic studies from our laboratory and others indicate that statin use is associated with both a reduced risk of clinical AD and reduced neurofibrillary tangle burden at autopsy. In addition, we recently demonstrated that 14 weeks of treatment with simvastatin (which has high central nervous system [CNS] penetration) reduced CSF levels of t-tau and p-tau181 in cognitively normal hypercholesterolemic subjects while treatment with pravastatin (which has low CNS penetration) did not. This pilot study provided valuable "proof-of-concept" evidence that using CSF AD biomarkers as clinical trial endpoints is both safe and feasible. The study proposed here is a 1-year fixed dose, randomized, placebo-controlled trial to evaluate the effects of simvastatin (40 mg/d) vs. placebo on CSF AD biomarkers in middle-aged (45-64 years) cognitively normal subjects (N=50 per group). Primary outcome measures are CSF t-tau, p-tau181, A¿42 and brain derived neurotropic factor (BDNF). Secondary outcome measures include inflammatory markers (Interleukin [IL]-6, IL-8, S1002), and oxidative stress markers (F2-isoprostanes) and the brain cholesterol metabolite (24S-hydroxycholesterol). Study outcomes and cognitive safety assessments (psychometric measures of simple and sustained attention, working and declarative memory, and complex reasoning) will be measured prior to and at 12 months of treatment. Adverse effects (including serum lipids, liver function tests, and creatine phosphokinase levels) will be monitored at 6-weeks and at 3-, 6-, and 12-months. The findings of the proposed study may provide support for conducting large-scale primary prevention trials in persons at high risk for AD using CSF biomarker as primary outcome measures. PUBLIC HEALTH RELEVANCE: Primary prevention of Alzheimer disease (AD) promises both clinical benefits for patients and their families and substantial economic benefits for society. Delaying the onset of AD by 5 years would reduce the number of AD cases by 50% in a generation, saving billions of health care dollars. Simvastatin has been widely used for prevention of coronary artery disease. The findings of the proposed study may provide proof of concept in support of large scale primary prevention trials in persons at high risk for AD.