To better understand the role of cholesterol homeostasis and CYP46A1 in relation to MS progression, we have: (i) analysed cholesterol and a selection of sterol intermediates involved in its synthesis and metabolism in both the plasma and cerebrospinal fluid (CSF) from people with MS who later experienced disability; (ii) used mass spectrometry imaging and lipid extraction techniques to show the extent of cholesterol and sterol dysbalance in post‐mortem cases of active progressive MS, and (iii) quantified CYP46A1 messenger RNA (mRNA) expression in normal and lesioned MS grey matter (GM). This evidence concerns the gene CYP46A1 and myeloid sarcoma.