Understanding mechanisms and seeking novel biomarkers in Alzheimer's disease

在去年的报告期内，我们发表了与FTO基因中常见变异相关的肥胖遗传风险与几种中间表型（如冲动性，饮食模式和衰老期间的脑功能）之间的关系。如果我们要发展针对生活方式相关风险因素（如肥胖）的行为干预措施，了解肥胖遗传风险的多效性是至关重要的。 我们已经研究了中年肥胖和AD发病年龄之间的关系以及与AD病理学的关系。我们首次报道中年肥胖会加速AD的发病，并使大脑中的AD神经病理学恶化。 我们研究了状态（即血清维生素D浓度）和性状（即编码维生素D结合蛋白DBP的基因的遗传变异）作为衰老过程中脑功能和结构的调节剂。 在我们的生物标志物研究中，我们报道了阿尔茨海默病（AD）患者血浆中三种磷脂酰胆碱（PC）分子的耗竭。我们随后扩展了这些发现，以测试它们与非痴呆老年人的认知表现以及与脑功能（通过静息态脑血流量测量; rCBF）的相关性。我们已经证明，这些PC的血浆浓度的降低也与衰老期间认知能力的降低以及与高阶认知处理相关的几个脑区的rCBF/脑功能的降低相关。我们的研究结果表明，外周PC代谢的扰动可能是AD以及与年龄相关的认知表现的共同特征。 我们已经完成了临床前AD的最大的血液生物标志物研究之一，使用血清代谢组学分析。在这里，我们分析了通过巴尔的摩老龄化纵向研究（BLSA）和年龄，基因/环境易感性-雷克雅未克研究（AGES-Reykjavik）收集的近800个系列血清样本。 我们还使用了多平台代谢组学方法，使用质谱和核磁共振来发现AD中的脑脊液生物标志物。 使用高密度人类蛋白质阵列，我们正在研究血清自身免疫特征的变化作为临床前AD的生物标志物。 靶向和全局代谢组学以及串联质量标记（TMT）-蛋白质组学方法目前正被用于研究尸检脑组织样本中AD病理学认知弹性的分子基础。

Over the reporting period for the last year, we have published on the relationships between genetic risk for obesity associated with a common variant in the FTO gene and several intermediate phenotypes such as impulsivity, dietary patterns and brain function during aging. Understanding the pleiotropic effects of genetic risk underlying obesity is critical if we are to develop behavioral interventions targeting life-style related risk factors such as obesity. We have examined the relationships between midlife obesity and the age-at-onset of AD as well as its relationship with AD pathology. We report, for the first time that midlife obesity accelerates the onset of AD and worsens AD neuropathology in the brain. We have studied both state (i.e. serum vitamin-D concentrations) and trait (i.e. genetic variations in the gene encoding vitamin-D binding protein, DBP) as modulators of brain function and structure during aging. In our biomarker studies, we have reported on the depletion of three phosphatidylcholine (PC) molecules in the plasma of patients with Alzheimer's disease (AD). We have subsequently extended these findings to test their association with cognitive performance in non-demented older individuals as well as with brain function (measured by resting state cerebral blood flow; rCBF). We have shown that a decrease in plasma concentrations of these PCs is also associated with lower cognitive performance during aging as well as with reduction in rCBF/brain function in several brain regions associated with higher order cognitive processing. Our findings suggest that perturbations in peripheral PC metabolism may be a common feature of both AD as well as age-associated cognitive performance. We have completed one of the largest blood biomarker studies of preclinical AD using metabolomics analyses of serum. Here, we analyzed nearly 800 serial serum samples collected through the Baltimore Longitudinal Study of Aging (BLSA) and the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik). We also used a multi-platform metabolomics approach using mass spectrometry and nuclear magnetic resonance to discover cerebrospinal fluid biomarkers in AD. Using high-density human protein arrays, we are investigating changes in serum autoimmune signatures as biomarkers of preclinical AD. Both targeted and global metabolomics as well as tandem mass tagging (TMT)-proteomics methods are currently being used to investigate the molecular bases of cognitive resilience to AD pathology in autopsy-derived brain tissue samples.