👤 James P Garrahy

Late-onset Alzheimer's disease (LOAD) is framed here as progressive astrocyte-neuronal metabolic and neurovascular uncoupling initiated by astrocytic bioenergetic collapse. In genetically or environmentally predisposed brains, a self-reinforcing loop of lipid accumulation, inflammation, vascular impairment, glucose-handling defects, and mitochondrial dysfunction erodes astrocytic functional capacity. Subsequent cerebrovascular dysfunction and loss of blood-brain barrier (BBB) integrity perpetuate the neuroinflammatory response and drive amyloid-β deposition. Astrocytic failure then disrupts astrocyte-neuron metabolic and neurovascular coupling, compromising lactate shuttling, glycogen mobilization, glutamate uptake, potassium buffering, antioxidant support, lipid handling, and demand-perfusion matching. Neurons deprived of this support enter chronic energy stress with sustained AMPK activation, which enhances tau hyperphosphorylation, perturbs proteostasis, and reduces tau Show less