Research has revealed scarcely any biological factors of Alzheimer's disease (AD) that are specific to men. Here, we found that the extreme downregulation of chromosome Y (EDY) increases the age-related risk of AD in men. We considered that EDY was a possible male-specific pathway toward AD because EDY is the most likely consequence of the mosaic loss of chromosome Y, which has been recently associated with AD. We studied EDY in the undiseased brain of 371 individuals and observed that it co-occurred across multiple brain regions (p < 10-4) and associated with rs114241159 (p = 1.53 × 10-7) within ACSS3/PPFIA2, previously linked to amyloid beta concentrations. We also analyzed the 5 largest transcriptomic case-control studies, publicly available to date on AD (cases/controls = 556/462) and found a significant interaction with age (OREDY × age = 1.22, p = 0.0038). Our analyses suggest that aging men who live longer by avoiding EDY are more resilient to AD than those who do not.

中文翻译：

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男性 Y 染色体极度下调与阿尔茨海默病

研究表明，几乎没有任何针对男性的阿尔茨海默病 (AD) 生物学因素。在这里，我们发现 Y 染色体 (EDY) 的极度下调会增加男性患 AD 的年龄相关风险。我们认为 EDY 可能是通往 AD 的男性特异性途径，因为 EDY 最有可能是 Y 染色体镶嵌丢失的结果，而 Y 染色体最近已与 AD 相关联。我们研究了 371 名个体未患病大脑中的 EDY，并观察到它在多个大脑区域同时发生 (p < 10-4) 并与 ACSS3/PPFIA2 中的 rs114241159 (p = 1.53 × 10-7) 相关，之前与淀粉样蛋白相关β 浓度。我们还分析了 5 个最大的转录组病例对照研究，迄今为止在 AD 上公开可用（病例/对照 = 556/462）并发现与年龄有显着的相互作用（OREDY × 年龄 = 1.22，p = 0.0038）。我们的分析表明，通过避免 EDY 而活得更久的老年男性比那些不这样做的人更能抵御 AD。