Leveraging Heterogeneity in Autosomal Dominant AD to Elucidate Pathophysiology and Improve AD Biomarkers

项目摘要： 阿尔茨海默病（AD）和相关痴呆（ADRD）对患者来说是巨大的负担， 家庭和卫生保健系统，强调迫切需要有效的，广泛的，和成本- 有效的疾病缓解疗法。更长的、易于聚集的Ab片段的过度产生（特别是 相对于较短的非聚集片段（尤其是Ab 37和38），Ab 42和43）似乎是关键的 在迟发性、散发性AD（LOAD）和常染色体显性AD（ADAD）中引发病理事件。 聚集和非聚集形式的Ab的产生之间的平衡是 γ-分泌酶复合物顺序切割β-淀粉样前体蛋白的效率和动力学 （APP）。γ-分泌酶功能的细微改变可导致严重的神经退行性和认知功能障碍。 结果，而γ-分泌酶的调节在LOAD和ADAD中具有治疗潜力。200多 早老素-1（PS1）是γ-分泌酶复合物中的关键催化亚基， 它是ADAD最常见的原因。尽管几乎完全昏迷， 症状发作年龄（范围>30岁）和认知和生物标志物变化率的异质性 PS1的变种。在这个建议中，我们假设，γ-分泌酶功能的差异， 在基于细胞的、生物化学的和初级神经元模型系统中测量的ADAD引起的PS1突变将 有助于解释症状发作年龄、认知和PS1中观察到的生物标志物变化的异质性 体内致病性变异载体。我们通过γ-分泌酶的系统表征来验证这一假设 在PS1致病变异体中的功能，并比较所得的免疫测定和质谱 测量G-分泌酶功能对来自相应PS1变体携带者的认知和生物标志物数据的影响 参与显性遗传阿尔茨海默氏症网络观察研究（DIAN-Obs），一个大型的 在一项国际研究中，有超过80种独特的PS1致病性变体。确定哪些 γ-分泌酶功能的变体特异性差异转化为症状出现年龄的差异， PS1携带者的认知和生物标志物轨迹代表了阐明AD的独特机会 病理生物学，为治疗和生物标志物开发提供信息，并影响ADAD临床试验。

Project Abstract: Alzheimer’s disease (AD) and related dementias (ADRD) represent an enormous burden for patients, families, and health care systems, underscoring the urgent need for efficacious, widely-accessible, and cost- effective disease-modifying therapies. The over-production of longer, aggregation-prone Ab fragments (esp. Ab42 and 43) relative to shorter, non-aggregating fragments (esp. Ab37 and 38) appears to be a critical initiating pathological event in both late-onset, sporadic AD (LOAD) and Autosomal Dominant AD (ADAD). The balance between production of aggregating and non-aggregating forms of Ab is a direct result of the efficiency and kinetics with which the γ-secretase complex sequentially cleaves b-amyloid precursor protein (APP). Subtle alterations in γ-secretase function can have profound neurodegenerative and cognitive consequences, while modulation of γ-secretase has therapeutic potential in both LOAD and ADAD. Over 200 pathogenic variants in Presenilin-1 (PS1), the key catalytic subunit in the γ-secretase complex, have been identified and are the most common cause of ADAD. Despite near complete penetrance, there is substantial heterogeneity in age of symptom onset (a range of >30 years) and rates of cognitive and biomarker change between PS1 variants. In this proposal, we hypothesize that differences in γ-secretase function between ADAD-causing PS1 mutations measured in cell-based, biochemical, and primary neuronal model systems will help explain heterogeneity in age of symptom onset, cognitive, and biomarker changes seen in PS1 pathogenic variant carriers in vivo. We test this hypothesis through systematic characterization of γ-secretase function across PS1 pathogenic variants and comparing the resulting immunoassay and mass spectroscopy measures of g-secretase function to cognitive and biomarker data from carriers of corresponding PS1 variants participating in the Dominantly Inherited Alzheimer’s Network Observational Study (DIAN-Obs), a large international study in which over 80 unique PS1 pathogenic variants are represented. Determining which variant-specific differences in γ-secretase function translate into differences in age of symptom onset and cognitive and biomarker trajectories in PS1 carriers represents a unique opportunity to elucidate AD pathobiology, inform therapeutic and biomarker development, and impact ADAD clinical trials.