The amyloid hypothesis for Alzheimer's disease (AD) posits a neuron-centric, linear cascade initiated by Aβ and leading to dementia. This direct causality is incompatible with clinical observations. We review evidence supporting a long, complex cellular phase consisting of feedback and feedforward responses of astrocytes, microglia, and vasculature. The field must incorporate this holistic view and take advantage of advances in single-cell approaches to resolve the critical junctures at which perturbations initially amenable to compensatory feedback transform into irreversible, progressive neurodegeneration.