Effects of Simvastatin on CSF AD biomarkers in cognitively normal subjects

描述(申请人提供)：阿尔茨海默病(AD)的初级预防有望带来巨大的临床和经济效益，但也带来了巨大的挑战，因为AD的病理过程早于痴呆的临床症状几年甚至几十年就开始了。使用脑脊液(CSF)AD生物标志物(例如，总tau[t-tau]、苏氨酸181[p-tau181]和A？42处的tau磷酸化)作为临床试验终点，可以在具有合理样本量和随访期的设计中展示假定的预防药物的疾病修改效果。辛伐他汀是一种安全和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，因为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临床AD风险的降低和尸检时神经原纤维缠绕负担的减少有关。此外，我们最近证明，在认知正常的高胆固醇血症受试者中，辛伐他汀(中枢神经系统渗透率高)治疗14周会降低脑脊液中t-tau和p-tau181的水平，而普伐他汀(中枢神经系统渗透率低)治疗则没有。这项先导性研究提供了有价值的“概念验证”证据，证明使用脑脊液AD生物标记物作为临床试验终点既安全又可行。这项研究是一项为期一年的固定剂量、随机、安慰剂对照试验，旨在评估辛伐他汀(40 mg/d)与安慰剂对认知正常的中年(45-岁)受试者(每组50人)脑脊液AD生物标志物的影响。主要观察指标为脑脊液t-tau、p-tau181、A？42和脑源性神经营养因子(BDNF)。次要观察指标包括炎症标记物(IL-6、IL-8、S1002)、氧化应激标记物(F2-异前列腺素)和脑胆固醇代谢产物(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指标)将在治疗前和治疗12个月时进行测量。不良反应(包括血脂、肝功能测试和肌酸磷酸激酶水平)将在6周、3个月、6个月和12个月监测。这项拟议的研究结果可能为在AD高危人群中进行大规模初级预防试验提供支持，使用脑脊液生物标记物作为主要结果指标。公共卫生相关性：阿尔茨海默病(AD)的初级预防承诺为患者及其家人带来临床好处，并为社会带来实质性的经济效益。将AD发病推迟5年将使一代人的AD病例减少50%，节省数十亿医疗保健资金。辛伐他汀已被广泛用于预防冠心病。这项拟议研究的结果可能为支持AD高危人群进行大规模一级预防试验提供概念证据。

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.