Overall, the overexpression of LB1 in ADLD cells alters nuclear mechanics and is linked to changes in nuclear signaling, which could help explain the pathogenesis of this disease.—Ferrera, D., Canale, C., Marotta, R., Mazzaro, N., Gritti, M., Mazzanti, M., Capellari, S., Cortelli, P., Gasparini, L. Lamin B1 overexpression increases nuclear rigidity in autosomal dominant leukodystrophy fibroblasts. Here, CKAP2 is linked to adult-onset autosomal dominant demyelinating leukodystrophy.