Deciphering hypothalamic pathology in ALS: insights into non-motor symptoms and disease progression

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with highly heterogeneous clinical presentations. Among the non-motor features increasingly recognised as clinically relevant is the dysregulation of energy balance, with weight loss-particularly due to fat mass loss-emerging as a significant modifier of disease risk, progression, and survival. In this context, the hypothalamus-a key regulator of homeostatic and metabolic processes-has gained attention for its potential role in ALS pathophysiology. This Review synthesises emerging evidence of hypothalamic involvement in ALS, including neuronal loss, proteinopathy, and volume loss observed through histological and neuroimaging studies. We critically examine current imaging approaches and their technical limitations and explore neuroendocrine dysfunction across the hypothalamic-pituitary axes. Collectively, these findings suggest that hypothalamic dysfunction may contribute to clinically relevant metabolic, sleep, behavioural, and cognitive changes in ALS, adding to our understanding of ALS as a multisystem disease. Continued investigation of the hypothalamus may reveal novel biomarkers, inform risk stratification, and identify therapeutic opportunities to address disease heterogeneity and improve clinical outcomes.