Energy and the Alzheimer brain.

The high energy demands of the poorly myelinated long axon hippocampal and cortical neurons render these neurons selectively vulnerable to degeneration in Alzheimer's disease. However, pathology engages all of the major elements of the neurovascular unit of the mature Alzheimer brain, the neurons, glia and blood vessels. Neurons present with retrograde degeneration of the axodendritic tree, capillaries with string vessels and markedly reduced densities and glia with signs of inflammatory activation. The neurons, capillaries and astrocytes of the mature Alzheimer brain harbor structurally defective mitochondria. Clinically, reduced glucose utilization, decades before cognitive deterioration, betrays ongoing energy insufficiency. β-hydroxybutyrate and γ-hydroxybutyrate can both provide energy to the brain when glucose utilization is blocked. Early work in mouse models of Alzheimer's disease demonstrate their ability to reverse the pathological changes in the Alzheimer brain and initial clinical trials reveal their ability to improve cognition and every day function. Supplying the brain with energy holds great promise for delaying the onset of Alzheimer's disease and slowing its progress.