Understanding mechanisms and seeking novel biomarkers in Alzheimer's disease

在过去一年的报告期内，我们发表了最近发现的新的AD风险基因与脑功能、病理和AD发病年龄(AAO)之间的关系。虽然我们之前报道了血浆聚集素(或载脂蛋白-J；apoJ)浓度与AD病理指标之间的关联，但最近我们研究了AD风险变异型聚集素基因(CLU)与衰老过程中脑功能纵向变化的关系。这项分析是在BLSA(BLSA-NI)的神经成像亚研究中进行的，并使用静息状态脑血流量(RCBF)来衡量脑功能的纵向变化。我们发现，即使携带一个或多个与AD相关的CLU风险等位基因的非痴呆老年人，与非风险等位基因携带者相比，大脑记忆回路中的rCBF也显示出显著更大的增量。 同样，虽然我们之前已经报道了几种补体相关蛋白的血浆浓度与AD病理之间的关联，但我们最近研究了AD风险变量补体受体-1(CR1)基因对BLSA-NI范围内非痴呆老年人脑淀粉样蛋白沉积的影响。我们发现，有些出乎意料的是，CR1的风险等位基因携带者实际上比非携带者显示出更低的大脑淀粉样蛋白负担。同样重要的是，我们报道了CR1和APOE基因之间的相互作用调节大脑淀粉样蛋白的负荷。这些发现对于引起人们对阿尔茨海默病潜在风险的替代的非淀粉样蛋白途径的关注是重要的，例如神经炎，以及研究基因x基因相互作用以更好地了解这些机制的必要性。 使用由国家阿尔茨海默病协调中心收集并通过NIAGADS获得的数据，我们检查了是否有任何新的AD风险基因影响AD的AAO。这种表型被认为具有不同于疾病风险的遗传性。在延缓阿尔茨海默病发病的战略背景下进行研究也很重要。我们发现，新的AD风险变异PICALM对AAO的影响很小，风险等位基因携带者在AD发病时显示出较低的年龄。 在其他研究中，我们发现在非痴呆者中，胰岛素抵抗(IR)与AD的病理程度无关，而中年IR与衰老过程中大脑功能的纵向变化有关。 在我们的生物标记物研究中，我们应用了新的技术，如人类蛋白质微阵列和抗体阵列相互作用图谱(AAIM)来识别与AD相关的新的蛋白质生物标记物和蛋白x蛋白相互作用。

Over the reporting period for the last year, we have published on the relationships between recently identified novel AD risk genes and measures of brain function, pathology and the age-at-onset (AAO) of AD. While we previously reported on the association between plasma concentration of clusterin (or apolipoprotein-J; apoJ) and measures of AD pathology, we recently examined the relationship between the AD risk variant clusterin gene (CLU) and longitudinal changes in brain function during aging. This analysis was performed in the neuroimaging substudy of the BLSA (BLSA-NI) and used resting state cerebral blood flow (rCBF) to measure longitudinal changes in brain function. We showed that even non-demented older individuals who carry one or more of the AD-related risk alleles of CLU show significantly greater increments in rCBF within memory circuits of the brain in comparison to risk allele non-carriers. Similarly, while we have previously reported on the association between plasma concentrations of several complement-related proteins and AD pathology, we recently studied the effect of the AD risk variant, Complement Receptor-1 (CR1) gene on brain amyloid deposition in non-demented older individuals within the BLSA-NI. We showed, somewhat unexpectedly, that risk allele carriers of CR1 actually show lower brain amyloid burden relative to non-carriers. Equally importantly, we reported that an interaction between the CR1 and APOE genes modulates brain amyloid burden. These findings are important in drawing attention to alternate, non-amyloid pathways underlying risk for AD, such as neuroinflammation as well as the need to study gene x gene interactions to gain a better understanding of such mechanisms. Using data collected by the National Alzheimers Disease Coordinating Center and available through NIAGADS, we examined whether any of the novel AD risk genes influence the AAO of AD. This phenotype is believed to have a heritability that is distinct from disease risk. It is also important to study in the context of strategies to delay the onset of AD. We showed that the novel AD risk variant PICALM exerts a small effect on the AAO, with risk allele carriers showing a lower age at onset of AD. In other studies, we showed that insulin resistance (IR) is not related to the extent of AD pathology in non-demented individuals and that midlife IR is associated with longitudinal changes in brain function during aging. In our biomarker studies, we have applied novel technology such as human protein microarrays and Antibody Array Interaction Mapping (AAIM) to identify novel protein biomarkers and protein x protein interactions associated with AD.