Table_6_Psychosis in Alzheimer's Disease Is Associated With Increased Excitatory Neuron Vulnerability and Post-transcriptional Mechanisms Altering Synaptic Protein Levels.XLSX

Alzheimer's disease with psychosis (AD+P) is a heritable phenotypic variant of the disease which is associated with more rapid cognitive deterioration compared to Alzheimer's disease without psychosis (AD–P). Cognitive decline in AD correlates with synapse loss, and our previous studies suggest that those with AD+P have a differentially affected synaptic proteome relative to those with AD–P. In this study, we utilized RNA-sequencing of dorsolateral prefrontal cortex (DLPFC) in a cohort of 80 AD cases to evaluate novel transcriptomic signatures that may confer risk of psychosis in AD. We found that AD+P was associated with a 9% reduction in excitatory neuron proportion compared to AD–P [Mean (SD) AD+P 0.295 (0.061); AD–P 0.324 (0.052), p = 0.026]. mRNA levels contributed only modestly to altered synaptic proteins in AD+P relative to AD–P. Instead, network analysis identified altered expression of gene modules from protein ubiquitination, unfolded protein response, eukaryotic initiation factor 2 (EIF2) signaling and endoplasmic reticulum stress pathways in AD+P. We previously found that neuropathologies account for ~18% of the variance in the occurrence of psychosis in AD. Further inclusion of cell type proportions and differentially expressed modules increased the percent of the variance in psychosis occurrence accounted for in our AD cohort to 67.5%.

伴精神病性症状的阿尔茨海默病（Alzheimer's disease with psychosis, AD+P）是该疾病的一种可遗传表型亚型，相较于无精神病性症状的阿尔茨海默病（Alzheimer's disease without psychosis, AD–P），其认知衰退速度更为迅速。阿尔茨海默病患者的认知衰退与突触丢失密切相关，我们此前的研究表明，与AD–P患者相比，AD+P患者的突触蛋白质组存在差异性改变。本研究针对80例阿尔茨海默病患者队列的背外侧前额叶皮层（dorsolateral prefrontal cortex, DLPFC）开展RNA测序，旨在探索可能增加阿尔茨海默病患者发生精神病性症状风险的新型转录组特征。我们发现，相较于AD–P患者，AD+P患者的兴奋性神经元占比降低9%[均值(标准差)：AD+P组0.295(0.061)；AD–P组0.324(0.052)，p=0.026]。相较于AD–P患者，AD+P患者突触蛋白的表达改变仅在较小程度上与mRNA水平变化相关。与之不同的是，网络分析揭示了AD+P患者中蛋白质泛素化、未折叠蛋白反应、真核起始因子2（eukaryotic initiation factor 2, EIF2）信号通路以及内质网应激通路相关基因模块的表达异常。我们此前的研究发现，神经病理改变仅能解释阿尔茨海默病患者精神病性症状发生变异的约18%。进一步纳入细胞类型占比以及差异表达基因模块后，本研究队列中精神病性症状发生变异的解释率提升至67.5%。