Metabolic signatures of ferritin and TDP-43 co-pathology provide a mechanistic basis for stratified therapeutic approaches in ALS

Metabolically distinct subtypes were defined by the presence or absence of ferritin-associated iron accumulation and TDP-43 pathology in the primary motor cortex.Concurrent ferritin and TDP-43 pathology produce a unique, metabolically decompensated state characterised by disrupted lipid, membrane, and energy metabolism, distinct from either pathology alone.Single positive states engage divergent compensatory metabolic pathways, which are lost when ferritin and TDP-43 co-occur.The metabolic signature of dual positivity provides a mechanistic correlate to the MRI-visible motor band sign.These findings support the use of pathology-based stratification of ALS patients and a foundation for pathway-targeted, precision therapeutic approaches.