Hohman Timothy J, Dumitrescu Logan, Cox Nancy J, Jefferson Angela L
Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center, 1207 17th Ave S, Suite 204F, Nashville, TN, 37212, USA.
Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Brain Imaging Behav. 2017 Apr;11(2):401-409. doi: 10.1007/s11682-016-9615-5.
Preclinical Alzheimer's disease (AD) is characterized by amyloid deposition in the absence of overt clinical impairment. There is substantial heterogeneity in the long-term clinical outcomes among amyloid positive individuals, yet limited work has focused on identifying molecular factors driving resilience from amyloid-related cognitive impairment. We apply a recently developed predicted gene expression analysis (PrediXcan) to identify genes that modify the association between baseline amyloid deposition and longitudinal cognitive changes. Participants free of clinical AD (n = 631) were selected from the AD Neuroimaging Initiative (ADNI) who had a baseline positron emission tomography measure of amyloid deposition (quantified as a standard uptake value ratio), longitudinal neuropsychological data, and genetic data. PrediXcan was used to impute gene expression levels across 15 heart and brain tissues. Mixed effect regression models assessed the interaction between predicted gene expression levels and amyloid deposition on longitudinal cognitive outcomes. The predicted gene expression levels for two genes in the coronary artery (CNTLN, PROK1) and two genes in the atrial appendage (PRSS50, PROK1) interacted with amyloid deposition on episodic memory performance. The predicted gene expression levels for two additional genes (TMC4 in the basal ganglia and HMBS in the aorta) interacted with amyloid deposition on executive function performance. Post-hoc analyses provide additional validation of the HMBS and PROK1 effects across two independent subsets of ADNI using two additional metrics of amyloid deposition. These results highlight a subset of unique candidate genes of resilience and provide evidence that cell-cycle regulation, angiogenesis, and heme biosynthesis likely play a role in AD progression.
临床前阿尔茨海默病（AD）的特征是在没有明显临床损伤的情况下出现淀粉样蛋白沉积。淀粉样蛋白阳性个体的长期临床结果存在很大的异质性，但专注于确定驱动抗淀粉样蛋白相关认知障碍的分子因素的研究工作有限。我们应用最近开发的预测基因表达分析（PrediXcan）来识别修饰基线淀粉样蛋白沉积与纵向认知变化之间关联的基因。从阿尔茨海默病神经影像学倡议（ADNI）中选取无临床AD的参与者（n = 631），他们有基线正电子发射断层扫描测量的淀粉样蛋白沉积（量化为标准摄取值比率）、纵向神经心理学数据和基因数据。PrediXcan用于估算15种心脏和脑组织中的基因表达水平。混合效应回归模型评估预测基因表达水平与淀粉样蛋白沉积在纵向认知结果上的相互作用。冠状动脉中的两个基因（CNTLN、PROK1）和心耳中的两个基因（PRSS50、PROK1）的预测基因表达水平与淀粉样蛋白沉积在情景记忆表现上存在相互作用。另外两个基因（基底神经节中的TMC4和主动脉中的HMBS）的预测基因表达水平与淀粉样蛋白沉积在执行功能表现上存在相互作用。事后分析使用另外两种淀粉样蛋白沉积指标对ADNI的两个独立亚组中的HMBS和PROK1效应进行了额外验证。这些结果突出了一组独特的抗逆候选基因，并提供证据表明细胞周期调节、血管生成和血红素生物合成可能在AD进展中起作用。
