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

描述（由申请人提供）：阿尔茨海默病（AD）是一种毁灭性的疾病，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AD的发病时间推迟五年的治疗可能会显着降低AD的患病率。中年时高血胆固醇水平增加了几十年后患AD的风险，可能是通过其对2-淀粉样蛋白（A2）代谢和脑血管功能障碍的负面影响。脑中A2沉积和脑血管失调是临床前AD病理学的两个早期发现，并协同作用加速神经元变性。因此，降低A2水平和改善脑血流量（CBF）的治疗可能会中断这种级联效应，以延迟AD的发展。在观察性研究中，使用称为他汀类的降胆固醇药物与AD患病率显著降低相关，这表明他汀类药物在AD预防中具有潜在的前景。他汀类药物降低动物脑脊液（CSF）和大脑中的A2水平，改善动物的CBF，但迄今为止的临床试验尚未最终表明他汀类药物有益地改变AD风险增加的无症状成人的A2代谢或CBF。基于先前的研究，我们提出了一项为期18个月的随机、对照、双盲的初步临床试验，评估辛伐他汀40 mg每日对无症状成人的CSF A2水平和脑灌注的影响，这些无症状成人由于父母有AD病史和载脂蛋白E 54（APOE 4）等位基因的高患病率而具有AD的高风险。对于本研究，CSF A242水平将是主要结局，但还将测量CSF A240、总tau和磷酸化tau以及其他新型CSF生物标志物，以提高A242预测基础疾病的能力。将使用动脉自旋标记磁共振成像（ASL-MRI）评估定量脑灌注。将收集CSF和MRI生物标志物的中期评估，以阐明长期他汀类药物治疗是否在改变AD进展的这些标志物方面具有累积效应。此外，这项初步临床试验将评估CSF A2代谢和CBF变化对认知指标的影响。这项试点临床试验的结果将有助于指导最终需要证明临床疗效的关键试验的发展。公共卫生相关性：如果辛伐他汀改善了AD发病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病中可能发挥作用的证据。如果他汀类药物预防或延迟AD的发作，它们不仅可能对数百万有疾病风险的个体患者的身体和情绪健康产生深远的影响，而且还可能对他们的家庭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.