Data_Sheet_1_Transcriptomic Changes Highly Similar to Alzheimer’s Disease Are Observed in a Subpopulation of Individuals During Normal Brain Aging.docx

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.

衰老是晚发性阿尔茨海默病（late-onset Alzheimer’s disease, LOAD）的主要风险因素。目前，衰老如何推动晚发性阿尔茨海默病的发生发展仍未阐明。本研究针对正常衰老及晚发性阿尔茨海默病患者的脑组织，分析了多套大规模转录组数据集，旨在揭示二者之间的分子关联机制。研究发现，衰老与晚发性阿尔茨海默病共有的基因表达改变主要集中于海马体及多个大脑皮层区域。在海马体中，衰老与阿尔茨海默病（Alzheimer’s disease, AD）共有的异常表达基因主要包括磷酸化蛋白、可变剪接及细胞骨架相关基因；而突触、离子转运及突触囊泡相关基因则普遍呈现下调表达。衰老特异性的表达改变与乙酰化及甲基化修饰相关；而晚发性阿尔茨海默病特异性的表达改变则更多与糖蛋白（上调及下调均存在）、炎症应答（上调）、髓鞘及脂蛋白（下调）相关。此外，本研究发现，来自较年轻供体（45~70岁）的正常衰老脑组织转录组可聚类为多个亚组，其中部分亚组的基因表达谱与晚发性阿尔茨海默病患者脑组织的表达谱高度相似。通过分析另一组老年个体（>70岁）的脑组织转录组数据集，本研究发现，认知正常的老年个体样本可聚类至"健康衰老"亚组，而阿尔茨海默病样本则主要聚类至"类阿尔茨海默病"亚组。这提示，属于"健康衰老"亚组的个体在衰老进程中大概率仍可维持认知正常，反之亦然。综上，本研究结果表明，在转录组层面，衰老与晚发性阿尔茨海默病在部分脑区中存在紧密的分子关联，且该关联主要存在于认知正常的衰老个体亚群中。该结果支持"晚发性阿尔茨海默病的发病启动早于临床表型显现数十年"这一假说，同时提示，深入研究"正常脑衰老"过程，对识别可能导致晚发性阿尔茨海默病发生的早期分子事件至关重要。