Leukocyte-derived Biomarkers as Predictors of Risk and Progression in AD

描述（由申请人提供）：阿尔茨海默病（AD）是一种慢性神经退行性疾病，临床上表现为老年人。有趣的是，各种死后证据表明，阿尔茨海默病的病理特征，以及由此推断的疾病本身，在个体生命的早期就开始出现。这导致了一种关于阿尔茨海默病的新观点，即一生中一系列不同的机制触发因素汇聚在共同的生化途径上，从而引发表型相似的临床综合征和神经病理状态。这种趋同的病理生理学假说认为，特定的下游生化途径介导了阿尔茨海默病中观察到的突触丧失、细胞损伤和死亡。此外，许多这些病理生理变化将在共享这些信号通路的外周系统中表现出来。我们假设造血系统与神经系统共享许多细胞信号通路，并受到许多与AD相同的病理生理变化的影响。具体来说，我们认为外周白细胞受到AD致病过程的影响，这将反映在蛋白质水平和功能的改变上。因此，这些变化将作为阿尔茨海默病诊断和进展的重要生物标志物，并将为其病理生理学和潜在治疗提供有价值的见解。我们建议从三个队列中确定并收集一系列临床测量和生物样本：轻度认知障碍(MCI)/AD高危受试者（年龄在75岁以上，有一级亲属诊断为AD）；年龄和性别匹配的低风险受试者；以及新诊断的MCI/AD患者。在Specific Aim 1中，我们将对所有发展为MCI/AD诊断的高风险受试者进行广泛的临床和生物分子检查，并与适当匹配的无MCI/AD的低风险受试者进行比较，以发现和验证潜在的疾病生物标志物特征。在Specific Aim 2中，我们将在没有MCI/AD的低风险队列和早期未使用药物的MCI/AD受试者的第二个亚群中测试该概况的特异性和敏感性。我们假设，在这些研究中确定的临床生物分子特征将对我们了解AD的疾病诊断、发病机制和治疗具有重要意义。随着美国婴儿潮一代的老龄化，充分了解这种疾病的发病机制、设计分子诊断和改进药物治疗对我们的国家和我们的医疗保健系统至关重要。因此，有必要开发强大的、特异的、敏感的早期AD生物标志物，这将极大地促进该疾病的诊断和治疗。公共卫生相关性：我们假设在这些研究中确定的临床生物分子特征将对我们了解AD的疾病诊断、发病机制和治疗非常重要。随着美国婴儿潮一代的老龄化，充分了解这种疾病的发病机制、设计分子诊断和改进药物治疗对我们的国家和我们的医疗保健系统至关重要。因此，有必要开发强大的、特异的、敏感的早期AD生物标志物，这将极大地促进该疾病的诊断和治疗。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a chronic neurodegenerative disorder that typically manifests clinically in the elderly. Interestingly, a variety of postmortem evidence suggests that the pathological hallmarks of AD, and by inference the disease itself, begin to occur early in an individual's life. This has led to an emerging view of AD whereby a set of disparate mechanistic triggers over a life-time converge upon shared biochemical pathways to elicit a phenotypically similar clinical syndrome and neuropathological state. This convergent pathophysiological hypothesis asserts that specific downstream biochemical pathways mediate the synaptic loss, cellular injury, and death observed in AD. Furthermore, many of these pathophysiological changes will be manifest in peripheral systems, which share these signaling pathways. We hypothesize that the hematopoietic system shares many cellular signaling pathways with the nervous system and is affected by many of the same pathophysiological changes that characterize AD. Specifically, we propose that peripheral leukocytes are affected by AD pathogenic processes, which will be reflected in alterations in protein levels and functions. As such, these changes will serve as important biomarkers for AD diagnosis and progression and will provide valuable insights into its pathophysiology and potential therapeutics. We propose to identify and collect serial clinical measurements and biological samples from three cohorts: subjects at high risk for developing mild-cognitive impairment (MCI)/AD (>75 years old with a first degree relative diagnosed with AD); age-and gender-matched subjects at low risk; and newly diagnosed, drug-naive subjects with MCI/AD. In Specific Aim 1 we will undertake an extensive clinical and biomolecular examination of all high risk subjects that progress to a diagnosis of MCI/AD compared to an appropriately matched subset of low risk subjects without MCI/AD to discover and validate a potential biomarker profile of disease. In Specific Aim 2 we will test the specificity and sensitivity of this profile in a second subset of the low risk cohort without MCI/AD and early, drug-naive MCI/AD subjects. We hypothesize that the clinical-biomolecular profile identified in these studies will be important to our understanding of disease diagnosis, pathogenesis, and therapy in AD. With the aging of America's baby boomers the need to fully understand the pathogenesis of this disease and to design molecular diagnostics and improved pharmacotherapies is vitally important to our nation and our health care systems. As such, it is necessary to develop robust, specific, and sensitive biomarkers of early AD, which would greatly facilitate the diagnosis and treatment of this disease. PUBLIC HEALTH RELEVANCE: We hypothesize that the clinical-biomolecular profile identified in these studies will be important to our understanding of disease diagnosis, pathogenesis, and therapy in AD. With the aging of America's baby boomers the need to fully understand the pathogenesis of this disease and to design molecular diagnostics and improved pharmacotherapies is vitally important to our nation and our health care systems. As such, it is necessary to develop robust, specific, and sensitive biomarkers of early AD, which would greatly facilitate the diagnosis and treatment of this disease.