AbstractAgeing is the greatest risk factor for dementia, although physiological ageing by itself does not lead to cognitive decline. In addition to ageing, APOE ε4 is genetically the strongest risk factor for Alzheimer’s disease and is highly expressed in astrocytes. There are indications that human astrocytes change with age and upon expression of APOE4. As these glial cells maintain water and ion homeostasis in the brain and regulate neuronal transmission, it is likely that age- and APOE4-related changes in astrocytes have a major impact on brain functioning and play a role in age-related diseases. In this review, we will discuss the molecular and morphological changes of human astrocytes in ageing and the contribution of APOE4. We conclude this review with a discussion on technical issues, innovations, and future perspectives on how to gain more knowledge on astrocytes in the human ageing brain.