DOMINANTLY INHERITED ALZHEIMER NETWORK TRIAL: AN OPPORTUNITY TO PREVENT DEMENTIA

描述（由申请人提供）：常染色体显性阿尔茨海默病（AD）已告知AD研究领域有关被认为是AD病理基础的分子和生化机制。此外，来自常染色体显性AD的突变提供了用于开发抗A β药物的动物和细胞模型。由于常染色体显性AD的罕见性，显性遗传阿尔茨海默病网络（DIAN; U 01 AG 032438）于2008年启动，以建立一个国际多中心登记研究，登记有风险的个体或在淀粉样前体蛋白（APP）、早老素1（PS1）或早老素2（PS2）基因中存在已知的AD致病突变的个体。DIAN在入组时和此后纵向评估参与者，使用临床和认知电池，结构，功能，代谢和淀粉样蛋白成像方案，以及生物液体（血液;脑脊液）收集，目的是确定注定发展为AD的症状前基因携带者的成像序列和生物标志物变化。由于显性遗传性AD的临床和病理表型似乎与更常见的迟发性“散发性”AD相似，显性遗传性AD中脑变化的性质和顺序也可能与散发性AD相关。试验设计是一项随机、盲法安慰剂对照的四组试验，试验对象为纤维状抗A β抗体、可溶性抗A β抗体和β分泌酶抑制剂i 160（每组n=40）无症状至轻度症状的ADAD突变携带者。受试者将接受两种药物或安慰剂治疗两年，以确定CNS作用机制和下游AD生物标志物的参与。

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.