Northwestern University Feinberg researchers reported a multiomic analysis showing ALS progresses through a “domino-like” cascade that starts in motor neurons and is amplified by immune infiltration from the periphery into the central nervous system. The work combines single-cell RNA sequencing of blood and spatial transcriptomics of spinal cord tissue from living and deceased participants, alongside postmortem RNA analysis in a larger ALS cohort. The study appeared in Nature Neuroscience. Researchers found immune cells converging at motor neuron loss sites and TDP-43 pathology, with inflammatory patterns varying by ALS type and progression speed. Lead investigators reported that the intensity of spinal cord inflammation correlated with how fast patients deteriorate and how long they survive. By tracing a peripheral-to-central immune trajectory, the findings could shape future therapeutic strategies toward immune modulation earlier in disease, potentially improving personalization for different ALS subtypes.