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

描述(申请人提供)：阿尔茨海默病(AD)是一种慢性神经退行性疾病，通常表现在老年人的临床上。有趣的是，各种尸检证据表明，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发生。这导致了对AD的一种新兴观点，即一生中一系列不同的机械触发因素汇聚在共同的生化途径上，导致表型相似的临床综合征和神经病理状态。这一趋同的病理生理学假说认为，特定的下游生化通路介导了AD患者的突触丢失、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，并受到许多相同的病理生理变化的影响，这些变化是AD的特征。具体地说，我们提出外周血白细胞受到AD致病过程的影响，这将反映在蛋白质水平和功能的变化上。因此，这些变化将成为AD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的治疗方法提供有价值的见解。我们建议从三个队列中识别和收集一系列临床测量和生物样本：患轻度认知损害(MCI)/AD的高危受试者(&gt；75岁，一级亲属被诊断为AD)；年龄和性别匹配的低风险受试者；以及新诊断的未服用药物的MCI/AD受试者。在具体目标1中，我们将对所有进展为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，并与适当匹配的非MCI/AD的低风险受试者子集进行比较，以发现和验证潜在的疾病生物标记物特征。在具体目标2中，我们将在没有MCI/AD的低风险队列的第二个子集和早期未服用药物的MCI/AD受试者中测试这一特征的特异性和敏感性。我们假设，这些研究中确定的临床-生物分子图谱将对我们理解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，需要充分了解这种疾病的发病机制，设计分子诊断方法和改进的药物疗法，这对我们的国家和我们的医疗保健系统至关重要。因此，有必要开发可靠、特异和敏感的早期AD生物标志物，这将极大地促进该病的诊断和治疗。公共卫生相关性：我们假设，这些研究中确定的临床-生物分子图谱将对我们理解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，需要充分了解这种疾病的发病机制，设计分子诊断方法和改进的药物疗法，这对我们的国家和我们的医疗保健系统至关重要。因此，有必要开发可靠、特异和敏感的早期AD生物标志物，这将极大地促进该病的诊断和治疗。

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.