Statin Effects on Beta-Amyloid and Cerebral Perfusion in Adults at Risk for AD

描述(申请人提供)：阿尔茨海默病(AD)是一种破坏性疾病，除非制定有效的预防策略，否则在未来几十年内将影响越来越多的老年人。将阿尔茨海默病的发病推迟五年的治疗方法可能会显著降低阿尔茨海默病的患病率。中年的高血胆固醇水平增加了几十年后发展为阿尔茨海默病的风险，可能是通过它们对2-淀粉样蛋白(A2)代谢和脑血管功能障碍的负面影响。A2在大脑中的沉积和脑血管调节失调都是临床前AD病理中的两个早期发现，并协同作用加速神经元退化。因此，同时降低A2水平和改善脑血流(CBF)的治疗可能会中断这种级联效应，以延缓AD的发展。在观察性研究中，他汀类降胆固醇药物的使用与AD患病率的显著降低有关，这表明他汀类药物在预防AD方面具有潜在的前景。他汀类药物可降低动物脑脊液(CSF)和大脑中的A2水平，并改善动物的脑血流，但迄今为止的临床试验尚未确凿地表明，他汀类药物对无症状的AD风险增加的成年人有益地改变A2代谢或脑血流。在既往研究的基础上，我们提出了一项为期18个月的随机、对照、双盲临床试验，评估每天服用辛伐他汀40 mg对无症状的AD高危成年人脑脊液A2水平和脑血流灌注的影响，这些人是由于父母有AD病史和载脂蛋白E 54(APOE4)等位基因的高患病率。对于这项研究，脑脊液A242水平将是主要结果，但脑脊液A240、总tau和磷酸化tau以及其他新的脑脊液生物标志物也将被检测，以提高A242预测潜在疾病的能力。定量脑血流灌注将使用动脉自旋标记磁共振成像(ASL-MRI)进行评估。将收集脑脊液和核磁共振生物标记物的中期评估，以澄清长期他汀类药物治疗在修改这些AD进展标记物方面是否具有累积效应。此外，这项试点临床试验将评估脑脊液A2代谢和脑血流变化对认知测量的影响。这项试点临床试验的结果将有助于指导最终证明临床疗效所需的关键试验的发展。与公共健康相关：如果辛伐他汀改善了阿尔茨海默病发作前几十年大脑中发生的一些变化，这些发现将加强他汀类药物在预防阿尔茨海默氏症中可能发挥作用的证据。如果他汀类药物预防或延缓阿尔茨海默病的发病，它们不仅可能对数百万有患病风险的患者的身心健康产生深远影响，还会对他们的家人和照顾者产生深远的影响。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating illness that will affect an increasing number of older adults in the coming decades unless effective preventive strategies are developed. Therapies that delay the onset of AD by just five years may reduce the prevalence of AD significantly. High blood cholesterol levels in midlife increase the risk of developing AD decades later, possibly via their negative effects on 2-amyloid (A2) metabolism and cerebrovascular dysfunction. Both A2 deposition in the brain and cerebrovascular dysregulation are two early findings in preclinical AD pathology and work synergistically to accelerate neuronal degeneration. Thus, therapies that both reduce A2 levels and improve cerebral blood flow (CBF) may interrupt this cascade effect to delay the development of AD. Use of cholesterol-lowering medications called statins has been associated with a significant reduction in the prevalence of AD in observational studies, suggesting a potentially promising role for statins in AD prevention. Statins lower A2 levels in the cerebrospinal fluid (CSF) and brains of animals and improve CBF in animals, but clinical trials to date have not shown conclusively that statins beneficially modify A2 metabolism or CBF in asymptomatic adults at increased risk for AD. Building upon previous investigations, we propose an 18-month randomized, controlled, double-blind pilot clinical trial evaluating the effects of simvastatin 40 mg daily on CSF A2 levels and cerebral perfusion in asymptomatic adults at high risk for AD due to their parental history of AD and high prevalence of apolipoprotein E 54 (APOE4) allele. For this study, CSF A242 levels will be the primary outcome, but CSF A240, total tau and phosphorylated tau, and other novel CSF biomarkers will also be measured to increase the ability of A242 to predict underlying disease. Quantitative cerebral perfusion will be assessed using arterial spin-labeling magnetic resonance imaging (ASL-MRI). Interim assessments of CSF and MRI biomarkers will be collected to clarify whether longer term statin therapy has a cumulative effect in modifying these markers of AD progression. In addition, this pilot clinical trial will evaluate the impact of changes in CSF A2 metabolism and CBF on cognitive measures. The findings from this pilot clinical trial will help guide the development of pivotal trials ultimately needed to demonstrate clinical efficacy. PUBLIC HEALTH RELEVANCE: If simvastatin improves some of the changes that occur in the brain decades before the onset of AD, these findings would strengthen the evidence that there may be a role for statins in Alzheimer's prevention. If statins prevent or delay the onset of AD, they could have a profound impact not only on the physical and emotional health of millions of individual patients at risk for the disease, but also on their families and caregivers.