The clinical manifestations of amyotrophic lateral sclerosis (ALS) are variable in terms of age at disease onset, site of onset, progression of symptoms, motor neuron involvement, and the occurrence of cognitive and behavioral changes. Genetic background is a key determinant of the ALS phenotype. The mortality of the disease also varies with the ancestral origin of the affected population and environmental factors are likely to be associated with ALS at least within some cohorts. Disease heterogeneity is likely underpinned by the presence of different pathogenic mechanisms. A variety of ALS animal models can be informative about the heterogeneity of the neuropathological or genetic aspects of the disease and can support the development of new therapeutic intervention. Evolving biomarkers can contribute to the identification of differing genotypes and phenotypes, and can be used to explore whether genotypic and phenotypic differences in animal models might help to provide a better definition of the heterogeneity of ALS in humans. These include neurofilaments, peripheral blood mononuclear cells, extracellular vesicles, microRNA and imaging findings. These biomarkers might predict not only the development of the disease, but also the variability in progression, although robust validation is required. A promising area of progress in modeling the heterogeneity of human ALS is represented by the use of human induced pluripotent stem cell (iPSCs)-derived motor neurons. Although the translational value of iPSCs remains unclear, this model is attractive in the perspective of replicating the heterogeneity of sporadic ALS as a first step toward a personalized medicine strategy.

肌萎缩侧索硬化 (ALS) 的临床表现因发病年龄、发病部位、症状进展、运动神经元受累以及认知和行为改变的发生而异。遗传背景是 ALS 表型的关键决定因素。该疾病的死亡率还因受影响人群的祖先起源而异，并且环境因素可能至少在某些队列中与 ALS 相关。疾病异质性可能是由不同致病机制的存在所支持的。各种 ALS 动物模型可以提供有关该疾病神经病理学或遗传方面异质性的信息，并可以支持新治疗干预的开发。不断发展的生物标志物有助于识别不同的基因型和表型，并可用于探索动物模型中的基因型和表型差异是否有助于更好地定义人类 ALS 的异质性。这些包括神经丝、外周血单核细胞、细胞外囊泡、microRNA 和成像结果。尽管需要强有力的验证，但这些生物标志物不仅可以预测疾病的发展，还可以预测进展的可变性。人类诱导多能干细胞 (iPSC) 衍生的运动神经元的使用代表了模拟人类 ALS 异质性的一个有前途的领域。尽管 iPSC 的转化价值尚不清楚，