Women have a higher incidence of Alzheimer’s disease (AD), even after adjusting for increased longevity. Thus, there is an urgent need to identify genes that underpin sex-associated risk of AD. PIN1 is a key regulator of the tau phosphorylation signaling pathway; however, potential differences in PIN1 expression, in males and females, are still unknown. We analyzed brain transcriptomic datasets focusing on sex differences in PIN1 mRNA levels in an aging and AD cohort, which revealed reduced PIN1 levels primarily within females. We validated this observation in an independent dataset (ROS/MAP), which also revealed that PIN1 is negatively correlated with multiregional neurofibrillary tangle density and global cognitive function in females only. Additional analysis revealed a decrease in PIN1 in subjects with mild cognitive impairment (MCI) compared with aged individuals, again driven predominantly by female subjects. Histochemical analysis of PIN1 in AD and control male and female neocortex revealed an overall decrease in axonal PIN1 protein levels in females. These findings emphasize the importance of considering sex differences in AD research.

中文翻译：

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女性阿尔茨海默病患者新皮质和边缘脑区域 PIN1 表达减少与认知和神经病理表型相关


即使在根据寿命延长进行调整后，女性患阿尔茨海默病 (AD) 的发病率也更高。因此，迫切需要确定与性别相关的 AD 风险的基因。 PIN1 是 tau 磷酸化信号通路的关键调节因子；然而，男性和女性 PIN1 表达的潜在差异仍然未知。我们分析了大脑转录组数据集，重点关注衰老和 AD 队列中 PIN1 mRNA 水平的性别差异，结果表明 PIN1 水平主要在女性中降低。我们在独立数据集 (ROS/MAP) 中验证了这一观察结果，该数据还表明，仅在女性中，PIN1 与多区域神经原纤维缠结密度和整体认知功能呈负相关。进一步的分析显示，与老年人相比，轻度认知障碍 (MCI) 受试者的 PIN1 有所下降，这同样主要是由女性受试者驱动的。 AD 和对照男性和女性新皮质中 PIN1 的组织化学分析显示，女性轴突 PIN1 蛋白水平总体下降。这些发现强调了 AD 研究中考虑性别差异的重要性。