Understanding mechanisms and seeking novel biomarkers in Alzheimer's disease

在去年的报告期内，我们发表了最近发现的新型AD风险基因与AD的脑功能，病理学和发病年龄（AAO）之间的关系。虽然我们以前报道了聚集蛋白（或载脂蛋白-J; apoJ）的血浆浓度和AD病理学指标之间的关系，但我们最近研究了AD风险变体聚集蛋白基因（CLU）与衰老过程中脑功能纵向变化之间的关系。该分析在BLSA的神经影像子研究（BLSA-NI）中进行，并使用静息态脑血流量（rCBF）测量脑功能的纵向变化。我们发现，即使是携带一个或多个AD相关风险等位基因的非痴呆老年人，与风险等位基因非携带者相比，大脑记忆回路内的rCBF也显示出显著更大的增量。 同样，虽然我们以前报道了几种补体相关蛋白的血浆浓度与AD病理学之间的关联，但我们最近研究了AD风险变体补体受体-1（CR 1）基因对BLSA-NI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，CR 1的风险等位基因携带者实际上显示出相对于非携带者更低的脑淀粉样蛋白负荷。同样重要的是，我们报道了CR 1和APOE基因之间的相互作用调节大脑淀粉样蛋白负荷。这些发现对于引起人们对AD潜在风险的替代性非淀粉样蛋白途径（如神经炎症）的关注以及研究基因x基因相互作用以更好地了解此类机制的必要性非常重要。 利用国家阿尔茨海默病协调中心收集的数据和NIAGADS提供的数据，我们研究了是否有任何新的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。同样重要的是要研究在战略的背景下，以延迟AD的发作。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发病时表现出较低的年龄。 在其他研究中，我们发现胰岛素抵抗（IR）与非痴呆个体的AD病理程度无关，中年IR与衰老过程中脑功能的纵向变化相关。 在我们的生物标志物研究中，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），以确定新的蛋白质生物标志物和与AD相关的蛋白质x蛋白质相互作用。

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.