DOMINANTLY INHERITED ALZHEIMER NETWORK TRIAL: AN OPPORTUNITY TO PREVENT DEMENTIA

描述(申请人提供)：常染色体显性遗传性阿尔茨海默病(AD)已经向AD研究领域提供了关于AD的分子和生化机制的信息，这些机制被认为是AD的病理基础。此外，常染色体显性阿尔茨海默病的突变提供了用于开发抗A药物的动物和细胞模型。由于常染色体显性阿尔茨海默病的罕见，多米尼利遗传性阿尔茨海默病网络(DIAN；U01 AG032438)于2008年启动，以建立一个国际性的多中心登记册，登记AD的风险个体或已知AD淀粉样前体蛋白(APP)、早老素1(PS1)或早老素2(PS2)基因突变的个体。Dian通过临床和认知电池、结构、功能、代谢和淀粉样蛋白成像方案以及生物液(血液；脑脊液)收集对参与者进行入院时和之后的纵向评估，目的是确定注定要发展为阿尔茨海默病的症状前基因携带者的成像和生物标志物变化的顺序。由于显性遗传性AD的临床和病理表型与更为常见的晚发性散发性AD相似，因此显性遗传性AD的脑部改变的性质和顺序也可能与散发性AD有关。这项试验设计是一项随机、安慰剂对照的四组试验，包括一种纤维性抗-A抗体、一种可溶性抗-A抗体和一种β-分泌酶抑制剂I 160(每组40例)，从无症状的ADAD突变携带者到轻度症状的ADAD突变携带者。受试者将接受为期两年的安慰剂药物，以确定中枢神经系统作用机制和下游AD生物标记物的参与情况。

DESCRIPTION (provided by applicant): Autosomal dominant Alzheimer's disease (AD) has informed the field of AD research about the molecular and biochemical mechanisms that are believed to underlie the pathological basis of AD. Further, mutations from autosomal dominant AD have provided animal and cellular models that are utilized to develop anti-A¿ drugs. Due to the rarity of autosomal dominant AD, the Dominantly Inherited Alzheimer Network (DIAN; U01 AG032438) was launched in 2008 to establish an international, multicenter registry of individuals at risk or with a known causative mutation of AD in the amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2) genes. DIAN evaluates participants at entry and longitudinally thereafter with clinical and cognitive batteries, structural, functional, metabolic,and amyloid imaging protocols, and biological fluid (blood; cerebrospinal fluid) collection with the goal of determining the sequence of imaging and biomarker changes in presymptomatic gene carriers who are destined to develop AD. Because the clinical and pathological phenotypes of dominantly inherited AD appear similar to those for the far more common late-onset "sporadic" AD, the nature and sequence of brain changes in dominantly inherited AD are also likely relevant for sporadic AD. The trial design is a randomized, blinded placebo controlled four arm trial of a fibrillar anti-A¿ antibody, a soluble anti-A¿ antibody, and a beta-secretase inhibitor i 160 (n=40 per arm) asymptomatic to mildly symptomatic ADAD mutation carriers. Subjects will receive either drug of placebo for two years to determine engagement of the CNS mechanism of action and downstream AD biomarkers.