Alexander disease (AxD) is a rare neurodegenerative disorder caused by the mutations in glial fibrillary acidic protein (GFAP) gene. Rosenthal fiber formations in astrocytes are the pathological hallmarks of AxD. Astrocyte dysfunction in the AxD brain is considered to be involved in its pathogenesis. We have previously reported that in AxD model mice aberrant Ca2+ signals in astrocytes were associated with the upregulation of reactive phenotype. Reactive astrocytes are conditions that lead to morphological, functional, and molecular changes by responding to various pathological insults (trauma, inflammation, ischemia), and environmental stimuli. Recent technological advances in single-cell gene expression analysis have revealed that astrocytes have heterogeneity by indicating that they form sub population with different characteristics depending on the brain region, the growth development, aging stage, and the pathological condition. AxD astrocytes are also thought to constitute a heterogeneous population with diverse properties and functions. Moreover, it is presumed that AxD pathogenesis occur due to interactions with neurons and other glial cells, as well as the microenvironment in tissues. Research strategies based on these perspectives will help us understand AxD pathology better and may lead to the elucidation of disease modifiers and clinical diversity.