Importance The X chromosome represents 5% of the human genome in women and men, and its influence on cognitive aging and Alzheimer disease (AD) is largely unknown. Objective To determine whether the X chromosome is associated with sex-specific cognitive change and tau pathology in aging and AD. Design, Setting, Participants This study examined differential gene expression profiling of the X chromosome from an RNA sequencing data set of the dorsolateral prefrontal cortex obtained from autopsied, elderly individuals enrolled in the Religious Orders Study and Rush Memory and Aging Project joint cohorts. Samples were collected from the cohort study with enrollment from 1994 to 2017. Data were last analyzed in May 2021. Main Outcomes and Measures The main analysis examined whether X chromosome gene expression measured by RNA sequencing of the dorsolateral prefrontal cortex was associated with cognitive change during aging and AD, independent of AD pathology and at the transcriptome-wide level in women and men. Whether X chromosome gene expression was associated with neurofibrillary tangle burden, a measure of tau pathology that influences cognition, in women and men was also explored. Results Samples for RNA sequencing of the dorsolateral prefrontal cortex were obtained from 508 individuals (mean [SD] age at death, 88.4 [6.6] years; 315 [62.0%] were female; 197 [38.8%] had clinical diagnosis of AD at death; 293 [58.2%] had pathological diagnosis of AD at death) enrolled in the Religious Orders Study and Rush Memory and Aging Project joint cohorts and were followed up annually for a mean (SD) of 6.3 (3.9) years. X chromosome gene expression (29 genes), adjusted for age at death, education, and AD pathology, was significantly associated with cognitive change at the genome-wide level in women but not men. In the majority of identified X genes (19 genes), increased expression was associated with slower cognitive decline in women. In contrast with cognition, X chromosome gene expression (3 genes), adjusted for age at death and education, was associated with neuropathological tau burden at the genome-wide level in men but not women. Conclusions and Relevance In this study, the X chromosome was associated with cognitive trajectories and neuropathological tau burden in aging and AD in a sex-specific manner. This is important because specific X chromosome factors could contribute risk or resilience to biological pathways of aging and AD in women, men, or both.

中文翻译：

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X 染色体与认知变化的性别特异性关联以及衰老和阿尔茨海默病中的 Tau 病理学。

重要性 X 染色体占女性和男性人类基因组的 5%，其对认知衰老和阿尔茨海默病 (AD) 的影响在很大程度上尚不清楚。目的 确定 X 染色体是否与衰老和 AD 中的性别特异性认知变化和 tau 病理相关。设计、背景、参与者 这项研究从参加宗教秩序研究和 Rush Memory and Aging Project 联合队列的老年人尸体解剖获得的背外侧前额叶皮质 RNA 测序数据集中检查了 X 染色体的差异基因表达谱。样本是从 1994 年至 2017 年入组的队列研究中收集的。最后一次分析数据是在 2021 年 5 月。主要结果和措施主要分析检查了通过背外侧前额叶皮层 RNA 测序测量的 X 染色体基因表达是否与认知变化相关。衰老和 AD，独立于 AD 病理学，并且在女性和男性的转录组水平上。还探讨了 X 染色体基因表达是否与神经原纤维缠结负担相关，神经原纤维缠结负担是影响女性和男性认知的 tau 病理学指标。结果 背外侧前额叶皮质 RNA 测序样本取自 508 名个体（死亡时平均 [SD] 年龄为 88.4 [6.6] 岁；315 名 [62.0%] 为女性；197 名 [38.8%] 死亡时临床诊断为 AD ; 293 名（58.2%）死亡时病理诊断为 AD）参加了宗教团体研究和 Rush Memory and Aging Project 联合队列，并每年进行平均 (SD) 6.3 (3.9) 年的随访。根据死亡年龄、教育程度和 AD 病理学进行调整后，X 染色体基因表达（29 个基因）与女性（而非男性）全基因组水平的认知变化显着相关。在大多数已识别的 X 基因（19 个基因）中，表达增加与女性认知能力下降较慢有关。与认知相反，根据死亡年龄和受教育程度调整后的 X 染色体基因表达（3 个基因）与男性全基因组水平的神经病理性 tau 负担相关，但与女性无关。结论和相关性 在这项研究中，X 染色体以性别特异性方式与衰老和 AD 中的认知轨迹和神经病理 tau 负担相关。这一点很重要，因为特定的 X 染色体因素可能会增加女性、男性或两者的衰老和 AD 生物学途径的风险或恢复能力。