Alzheimer's Disease as the Product of a Progressive Energy Deficiency Syndrome in the Central Nervous System: The Neuroenergetic Hypothesis

Abstract

The decreased availability of metabolizable energy resources in the central nervous system is hypothesized to be a key factor in the pathogenesis of Alzheimer's disease. More specifically, the age-related decline in the ability of glucose to cross the blood-brain barrier creates a metabolic stress that shifts the normal, benign processing of amyloid-β protein precursor toward pathways associated with the production of amyloid-β plaques and tau-containing neurofibrillary tangles that are characteristic of the disease. The neuroenergetic hypothesis provides insight into the etiology of Alzheimer's disease and illuminates new approaches for diagnosis, monitoring, and treatment.

Keywords: Alzheimer’s disease; GLUT1; alpha-secretase; amyloid-β; amyloid-β protein precursor; beta-hydroxy butyrate; beta-secretase; blood-brain barrier; gamma-secretase; glucose; neuroenergetic hypothesis; tau; type-3 diabetes.

Fig.1

The generation of products from the amyloid-β protein precursor (AβPP). During periods of central nervous system (CNS) energy adequacy, AβPP will get cleaved along a non-amyloidogenic pathway by the action of α-secretase to produce sAβPPα, which, after the action of γ-secretase, produces p3 peptides which have an ability to exit the CNS through the blood-brain barrier (BBB). During periods of CNS energy inadequacy, AβPP gets cleaved along an amyloidogenic pathway by the action of β-secretase to product sAβPPβ, which, after the action of γ-secretase, produces intact amyloid-β (Aβ) peptides that cannot effectively exit the CNS through the BBB, and are associated with the pathogenesis of Alzheimer’s disease. Adapted from [32] (CC BY 4.0).