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The lack of understanding of the cellular and molecular basis of clinical and genetic heterogeneity in progressive multiple sclerosis (MS) has hindered the search for new effective therapies. Here, to address this gap, we analysed 632,000 single nuclei RNAseq profiles of 156 brain tissue samples, comprising white matter (WM) lesions, normal appearing WM, grey matter (GM) lesions and normal appearing GM from 54 MS patients and 26 controls. We observed the expected changes in overall neuronal and glial numbers previously described within the classical lesion subtypes. We found highly cell type-specific gene expression changes in MS tissue, with distinct differences between GM and WM areas, confirming different pathologies. However, surprisingly, we did not observe distinct gene expression signatures for the classical different WM lesion types, rather a continuum of change. This indicates that classical lesion characterization better reflects changes in cell abundance than changes in cell type gene expression, and indicates a global disease effect. Furthermore, the major biological determinants of variability in gene expression in MS WM samples relate to individual patient effects, rather than to lesion types or other metadata. We identify four subgroups of MS patients with distinct WM glial gene expression signatures and patterns of oligodendrocyte stress and/or maturation, suggestive of engagement of different pathological processes, with an additional more variable regenerative astrocyte signature. The discovery of these patterns, which were also found in an independent MS patient cohort, provides a framework to use molecular …