Amyotrophic lateral sclerosis (ALS) is the most common form of human motor neuron disease. It is characterized by the progressive degeneration of upper and lower motor neurons, leading to generalized motor weakness and, ultimately, respiratory paralysis and death within 3–5 years. The disease is shaped by genetics, age, sex and environmental stressors, but no cure or routine biomarkers exist for the disease. Male individuals have a higher propensity to develop ALS, and a different manifestation of the disease phenotype, than female individuals. However, the mechanisms underlying these sex differences remain a mystery. In this Review, we summarize the epidemiology of ALS, examine the sexually dimorphic presentation of the disease and highlight the genetic variants and molecular pathways that might contribute to sex differences in humans and animal models of ALS. We advance the idea that sexual dimorphism in ALS arises from the interactions between the CNS and peripheral organs, involving vascular, metabolic, endocrine, musculoskeletal and immune systems, which are strikingly different between male and female individuals. Finally, we review the response to treatments in ALS and discuss the potential to implement future personalized therapeutic strategies for the disease.

肌萎缩侧索硬化症（ALS）是人类运动神经元疾病的最常见形式。其特点是上、下运动神经元进行性退化，导致全身运动无力，最终在 3-5 年内出现呼吸麻痹和死亡。这种疾病是由遗传、年龄、性别和环境压力因素决定的，但这种疾病尚无治疗方法或常规生物标志物。与女性个体相比，男性个体更容易发生 ALS，且疾病表型表现不同。然而，这些性别差异背后的机制仍然是个谜。在这篇综述中，我们总结了 ALS 的流行病学，检查了该疾病的性别二态性表现，并强调了可能导致 ALS 人类和动物模型性别差异的遗传变异和分子途径。我们提出这样的观点：ALS 的性别二态性源于中枢神经系统和周围器官之间的相互作用，涉及血管、代谢、内分泌、肌肉骨骼和免疫系统，这些系统在男性和女性个体之间存在显着差异。最后，我们回顾了 ALS 治疗的反应，并讨论了对该疾病实施未来个性化治疗策略的潜力。