Abstract: Alzheimer’s disease (AD) is the most frequent form of dementia in elderly people and is an incurable disease with an exponentially growing number of cases. Extracellular deposition of amyloid-β (Aβ) plaques and intraneuronal formation of neurofibrillary tangles represent neuropathological hallmarks of AD. A high failure rate of clinical trials, testing drugs aimed at either removal of Aβ or normalization of neuronal functions, suggests that the amyloid cascade hypothesis is not able to explain the complexity of AD pathogenesis, and the role of non-neuronal cells of the central nervous system, such as astroglial cells, should be considered. A significant advance in AD research has been the understanding that the pathogenesis, at a cellular level, starts much earlier than the appearance of clinical symptoms. Cellular remodeling includes alteration of protein synthesis, folding, and degradation, dysregulation of calcium homeostasis and signaling, mitochondrial alterations accompanied by bioenergetic deficit, and accumulation of reactive oxygen species. These alterations have been exploited to formulate numerous AD hypotheses, including the amyloid cascade and the inflammatory, vascular, and infectious factors, which, traditionally, have been developed and interpreted through the lens of neuronal dysfunction, while alterations of glial cells, such as astrocytes have been largely overlooked (Verkhratsky et al., 2019; Lim et al., 2023). Recently, dysregulation of inter-organellar communication, in particular, the mitochondria-endoplasmic reticulum (ER) interaction, both in neurons and non-neuronal cells, came to age as a potential cause of cellular dysfunction in AD and other diseases, such as Parkinson’s disease (Paillusson et al., 2016; Area-Gomez and Schon, 2017; Lim et al., 2021).