Table_4_Transcriptomic Changes Highly Similar to Alzheimer’s Disease Are Observed in a Subpopulation of Individuals During Normal Brain Aging.XLS

Aging is a major risk factor for late-onset Alzheimer’s disease (LOAD). How aging contributes to the development of LOAD remains elusive. In this study, we examined multiple large-scale transcriptomic datasets from both normal aging and LOAD brains to understand the molecular interconnection between aging and LOAD. We found that shared gene expression changes between aging and LOAD are mostly seen in the hippocampal and several cortical regions. In the hippocampus, the expression of phosphoprotein, alternative splicing and cytoskeleton genes are commonly changed in both aging and AD, while synapse, ion transport, and synaptic vesicle genes are commonly down-regulated. Aging-specific changes are associated with acetylation and methylation, while LOAD-specific changes are more related to glycoprotein (both up- and down-regulations), inflammatory response (up-regulation), myelin sheath and lipoprotein (down-regulation). We also found that normal aging brain transcriptomes from relatively young donors (45–70 years old) clustered into several subgroups and some subgroups showed gene expression changes highly similar to those seen in LOAD brains. Using brain transcriptomic datasets from another cohort of older individuals (>70 years), we found that samples from cognitively normal older individuals clustered with the “healthy aging” subgroup while AD samples mainly clustered with the “AD similar” subgroups. This may imply that individuals in the healthy aging subgroup will likely remain cognitively normal when they become older and vice versa. In summary, our results suggest that on the transcriptome level, aging and LOAD have strong interconnections in some brain regions in a subpopulation of cognitively normal aging individuals. This supports the theory that the initiation of LOAD occurs decades earlier than the manifestation of clinical phenotype and it may be essential to closely study the “normal brain aging” to identify the very early molecular events that may lead to LOAD development.

老化是晚发性阿尔茨海默病（LOAD）的主要风险因素。老化如何导致LOAD的发展尚属未知。在本研究中，我们分析了正常老化与LOAD脑部的大规模转录组数据集，旨在揭示老化与LOAD之间的分子相互作用。我们发现，老化与LOAD之间共有的基因表达变化主要见于海马体及多个皮层区域。在海马体中，磷酸蛋白、选择性剪接和细胞骨架基因在老化与AD中均出现表达改变，而突触、离子转运和突触小泡基因则普遍下调。特定于老化的变化与乙酰化和甲基化相关联，而特定于LOAD的变化则更多与糖蛋白（包括上调和下调）、炎症反应（上调）、髓鞘和脂蛋白（下调）相关。此外，我们还发现，来自相对年轻捐赠者（45-70岁）的正常老化脑部转录组聚类成几个亚组，其中一些亚组的基因表达变化与LOAD脑部所见高度相似。使用来自另一个老年个体队列（>70岁）的大脑转录组数据集，我们发现认知正常的老年个体的样本与“健康老化”亚组聚类，而AD样本主要与“AD相似”亚组聚类。这可能表明，在健康老化亚组的个体随着年龄增长将保持认知正常，反之亦然。总之，我们的研究结果提示，在转录组水平上，老化与LOAD在某些认知正常老化个体的脑部区域具有强烈的相互联系。这支持了LOAD的启动可能比临床表型显现早数十年的理论，并且深入研究“正常脑部老化”对于识别可能导致LOAD发展的非常早期分子事件至关重要。