Sex differences in the manifestations of Alzheimer’s disease are under intense investigation. Despite the emerging importance of polygenic predictions for Alzheimer’s disease, sex-dependent polygenic effects have not been demonstrated. Here, using a sex crossover analysis, we show that sex-dependent autosomal genetic effects on Alzheimer’s disease can be revealed by characterizing disease progress via the hazard function. We first performed sex-stratified genome-wide associations, and then applied derived sex-dependent weights to two independent cohorts. Relative to sex-mismatched scores, sex-matched polygenic hazard scores showed significantly stronger associations with age-at-disease-onset, clinical progression, amyloid deposition, neurofibrillary tangles, and composite neuropathological scores, independent of apolipoprotein E. Models without using hazard weights, i.e. polygenic risk scores, showed lower predictive power than polygenic hazard scores with no evidence for sex differences. Our results indicate that revealing sex-dependent genetic architecture requires the consideration of temporal processes of Alzheimer’s disease. This has strong implications not only for the genetic underpinning of Alzheimer’s disease but also for how we estimate sex-dependent polygenic effects for clinical use.

中文翻译：

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性别依赖性常染色体对阿尔茨海默病临床进展的影响。


阿尔茨海默病表现的性别差异正在深入研究中。尽管多基因预测对阿尔茨海默病的重要性日益凸显，但性别依赖性多基因效应尚未得到证实。在这里，我们使用性别交叉分析表明，通过风险函数表征疾病进展，可以揭示性别依赖性常染色体遗传对阿尔茨海默病的影响。我们首先进行了性别分层的全基因组关联，然后将派生的性别依赖性权重应用于两个独立的队列。相对于性别不匹配的评分，性别匹配的多基因风险评分与发病年龄、临床进展、淀粉样蛋白沉积、神经原纤维缠结和复合神经病理学评分的相关性显着更强，且与载脂蛋白 E 无关。 不使用风险权重的模型，即多基因风险评分，显示出比没有性别差异证据的多基因风险评分更低的预测能力。我们的结果表明，揭示性别依赖性遗传结构需要考虑阿尔茨海默病的时间过程。这不仅对阿尔茨海默病的遗传基础具有重要意义，而且对我们如何估计临床应用中的性别依赖性多基因效应也具有重要意义。