In recent clinical trials of pharmacological treatments, differential benefits have been noted in specific patient subgroups, often with more favourable results in patients with fast progressing amyotrophic lateral sclerosis. ...awareness of disease heterogeneity is increasing. ...there is a growing need to test novel pharmacological and genetic treatment approaches over a shorter trial period. A study by Maor-Nof and colleagues10 elucidated how the dipeptide protein poly-proline-arginine, which is generated from the repeat expansion, induces apoptotic pathways and, ultimately, neurodegeneration by epigenetic modulation of gene transcription via the transcription factor TP53, thereby indicating nucleoporin p54 ablation as a novel therapeutic strategy.10 Overall, amyotrophic lateral sclerosis research in 2021 has resulted in increasing knowledge on risk factors and mechanisms, and in advances in biomarker research and trial design.