A Systematic Review of Glucose Transport Alterations in Alzheimer's Disease

Introduction: Alzheimer's disease (AD) is characterized by cerebral glucose hypometabolism. Hypometabolism may be partly due to reduced glucose transport at the blood-brain barrier (BBB) and across astrocytic and neuronal cell membranes. Glucose transporters (GLUTs) are integral membrane proteins responsible for moving glucose from the bloodstream to parenchymal cells where it is metabolized, and evidence indicates vascular and non-vascular GLUTs are altered in AD brains, a process which could starve the brain of glucose and accelerate cognitive decline. Here we review the literature on glucose transport alterations in AD from human and rodent studies. Methods: Literature published between 1st January 1946 and 1st November 2020 within EMBASE and MEDLINE databases was searched for the terms “glucose transporters” AND “Alzheimer's disease”. Human and rodent studies were included while reviews, letters, and in-vitro studies were excluded. Results: Forty-three studies fitting the inclusion criteria were identified, covering human (23 studies) and rodent (20 studies). Post-mortem studies showed consistent reductions in GLUT1 and GLUT3 in the hippocampus and cortex of AD brains, areas of the brain closely associated with AD pathology. Tracer studies in rodent models of AD and human AD also exhibit reduced uptake of glucose and glucose-analogs into the brain, supporting these findings. Longitudinal rodent studies clearly indicate that changes in GLUT1 and GLUT3 only occur after amyloid-β pathology is present, and several studies indicate amyloid-β itself may be responsible for GLUT changes. Furthermore, evidence from human and rodent studies suggest GLUT depletion has severe effects on brain function. A small number of studies show GLUT2 and GLUT12 are increased in AD. Anti-diabetic medications improved glucose transport capacity in AD subjects. Conclusions: GLUT1 and GLUT3 are reduced in hippocampal and cortical regions in patients and rodent models of AD, and may be caused by high levels of amyloid-β in these regions. GLUT3 reductions appear to precede the onset of clinical symptoms. GLUT2 and GLUT12 appear to increase and may have a compensatory role. Repurposing anti-diabetic drugs to modify glucose transport shows promising results in human studies of AD.