Relationship between tau pathology and cognitive impairment in autosomal dominant Alzheimer's disease

项目总结 自从阿尔茨海默病(AD)被发现以来，第一次正在进行淀粉样蛋白修饰治疗 在临床试验中进行评估，而其他抗tau抗体和其他疾病修改治疗正在进行中 发展。这些治疗有望改变AD的病程，甚至预防其临床 如果及早用药，会有明显的表现。现在出现了三个迫切需要：1)改善我们的 使用生物标记物检测临床前AD和跟踪进展的能力，2)了解颞叶 淀粉样蛋白聚集、tau聚集和认知能力下降之间的关系，以及3)利用这一点 提高临床前治疗试验的效率和成功概率的信息。在这份提案中， 我们在哥伦比亚的安蒂奥基亚与大约5000人的非凡亲属合作，这是 包含大约1500名常染色体显性早衰素1(PSEN1)E280A突变的携带者。这些 携带者几乎肯定会发展为早发性阿尔茨海默病，并有明确的病程特征，轻度 认知障碍(MCI)的平均年龄为45岁，痴呆症的平均年龄为51岁。以前我们 使用横断面方法来表征生物标记物随年龄的变化以及与年龄的关系 Kindred的平均临床发病年龄。我们目前正在进行第一次横断面tau PET成像 和这一类人一起学习。这里提出的纵向数据的加入将极大地改善我们的 临床前ADAD中tau和淀粉样蛋白的时空轨迹及其相互关系的认识 导致随后的认知能力下降。这些数据将有助于预防试验的设计和分析， 包括正在进行的阿尔茨海默病预防倡议(API)常染色体显性AD(ADAD)试验。我们会 在基线、18个月和36个月时获取一组全面的神经成像和神经心理学数据 30名认知正常的PSEN1突变携带者(年龄30-45岁)，30名年龄匹配的非携带者家族 成员和20名认知障碍携带者(年龄40-55岁)。淀粉样蛋白有害的假说 对大脑的影响主要是通过促进tau的聚集来提供的，但有证据表明它是支持或反对的。 人类是有限的。我们假设在临床前期的ADAD中，皮质淀粉样变先于tau病理。 在内侧颞叶(MTL)。此外，tau应该比淀粉样蛋白与记忆的相关性更强。 网络中断并伴有认知障碍。将对所有科目进行评估，以实现以下目标 具体目的：1)研究tau病理在临床前ADAD记忆网络功能障碍中的作用；2) 确定淀粉样蛋白和tau病理的PET测量可用于预测预后的程度 随后认知衰退和临床进展的生物标记物；以及3)提供 临床前ADAD可以为AD试验设计提供信息。

PROJECT SUMMARY For the first time since Alzheimer's disease (AD) was discovered, amyloid-modifying treatments are being evaluated in clinical trials, while other anti-tau antibodies and other disease-modifying treatments are in development. These treatment hold promise to modify the course of AD, and even prevent its clinical manifestation, if administered early enough. Three urgent needs now present themselves: 1) to improve our ability to detect preclinical AD and track is progression using biomarkers, 2) to understand the temporal relationships between amyloid aggregation, tau aggregation and cognitive decline, and 3) to leverage that information to increase the efficiency and probability of success of preclinical treatment trials. In this proposal, we work with an extraordinary kindred of approximately 5,000 individuals in Antioquia, Colombia, which contains roughly 1500 carriers of the autosomal-dominant Presenilin1 (PSEN1) E280A mutation. These carriers are virtually certain to develop early onset AD, and have a well-characterized disease course, with mild cognitive impairment (MCI) occurring at a mean age of 45, and dementia at a mean age of 51. Previously we used a cross-sectional approach to characterize biomarker changes as a function of age, and in relation to the kindred's mean age of clinical onset. We are currently performing the first cross-sectional tau PET imaging study with this kindred. The addition of the longitudinal data proposed here will greatly improve our understanding of the temporal and spatial trajectories of tau and amyloid in preclinical ADAD, and their relation to subsequent cognitive decline. These data will help inform the design and analysis of prevention trials, including the ongoing Alzheimer's Prevention Initiative (API) autosomal-dominant AD (ADAD) trial. We will acquire a comprehensive set of neuroimaging and neuropsychological data at baseline, 18- and 36-months in 30 cognitively unimpaired PSEN1 mutation carriers (ages 30-45 years), 30 age-matched non-carrier family members, and 20 cognitively impaired carriers (ages 40-55 years). The hypothesis that amyloid exerts harmful effects on the brain mainly by facilitating tau aggregation has been offered, but evidence for or against it in humans is limited. We hypothesize that in preclinical ADAD, cortical amyloid pathology precedes tau pathology in the medial temporal lobe (MTL). Further, tau should correlate more strongly than amyloid with memory network disruption and with cognitive impairment. All subjects will be evaluated to accomplish the following specific aims: 1) Examine the role of tau pathology in memory network dysfunction in preclinical ADAD; 2) Determine the extent to which PET measures of amyloid and tau pathology can be used as prognostic biomarker for subsequent cognitive decline and clinical progression; and 3) Provide a biomarker profile of preclinical ADAD that can inform AD trial design.