Multiscale Transcriptomic Architecture of the ALS Motor Cortex

Seven reproducible ALS motor cortex transcriptomic subtypes were identified, and donor-held-out projection recovered subtype assignments with mean balanced accuracy of 0.939.

• Why it matters: ALS shows clinical and molecular heterogeneity, but pooled cross-region work can blur regional differences; motor cortex organization needed clearer, disease-relevant structure.
• What they did: Using ~600 postmortem motor cortex transcriptomes from Target ALS, gene set variation analysis and consensus clustering in pathway space defined subtype programs, then were tested on held-out donors and mapped to independent single-nucleus RNA-seq.
• The result: Subtypes formed a structured pathway-space landscape with discrete peaks and continuous gradients, aligned more with clinical/genetic-background variables than disease duration, including enrichment patterns by ALS/FTD family history and C9orf72 repeat expansion status.

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