The article reviews the cellular phase of Alzheimer's disease (AD), emphasizing the complexity and multifactorial nature of the disease. It challenges the traditional neuron-centric, linear cascade model of the amyloid hypothesis, which posits a direct causal link between Aβ deposition and dementia. Instead, it highlights the involvement of astrocytes, microglia, and the vasculature in a long, complex cellular phase characterized by feedback and feedforward responses. The authors argue that initial compensatory mechanisms can transform into irreversible neurodegeneration, and that the disease progression is influenced by aging and other cellular factors. They discuss the role of defective clearance mechanisms, the vascular hypothesis, and the cellular responses of neurons, astrocytes, and microglia. The article also explores the potential of systems biology approaches and single-cell analysis to better understand the cellular responses in AD, emphasizing the need for cellular resolution and temporal analysis.The article reviews the cellular phase of Alzheimer's disease (AD), emphasizing the complexity and multifactorial nature of the disease. It challenges the traditional neuron-centric, linear cascade model of the amyloid hypothesis, which posits a direct causal link between Aβ deposition and dementia. Instead, it highlights the involvement of astrocytes, microglia, and the vasculature in a long, complex cellular phase characterized by feedback and feedforward responses. The authors argue that initial compensatory mechanisms can transform into irreversible neurodegeneration, and that the disease progression is influenced by aging and other cellular factors. They discuss the role of defective clearance mechanisms, the vascular hypothesis, and the cellular responses of neurons, astrocytes, and microglia. The article also explores the potential of systems biology approaches and single-cell analysis to better understand the cellular responses in AD, emphasizing the need for cellular resolution and temporal analysis.