Vulnerable powerhouses: a staged model of astrocytic mitochondrial failure and energetic buffering collapse in Alzheimer's disease

Alzheimer's disease (AD) is defined biologically by amyloid-β and tau pathology, yet its earliest phases are marked by profound functional fragility, vascular dysfunction, and astrocytic mitochondrial stress. We propose that early AD can be interpreted as a progressive failure of astrocytic energetic buffering, determined primarily by a narrowing mitochondrial stability margin. Within this framework, astrocytes act as dynamic stabilizers of neural microdomains. They couple localized synaptic activity to glutamate clearance, potassium spatial buffering, and neurovascular signaling-processes that depend on specialized, compartmentalized mitochondrial ATP regeneration and calcium handling. We outline a four-stage model in which subclinical mitochondrial fragility precedes compensatory glycolytic overuse, lipid-and inflammation-linked reactive states, secondary amyloid/tau amplification, and eventual network decompensation. In this model, mitochondria are not merely collateral victims of AD pathology but are the central orchestrators of tissue recoverability.