Fueling the brain - the role of apolipoprotein E in brain energy metabolism and its implications for Alzheimer’s disease

The human brain has high energy demands and tightly regulated mechanisms ensure its activity-dependent energy supply. Glucose hypometabolism is associated with brain aging and has also been linked to neurodegenerative diseases such as Alzheimer's disease (AD). The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for AD while APOE2 reduces the risk and APOE3 has been referred to as risk neutral allele. APOE is a major lipid carrier in the brain and is not only involved in the build-up of the two AD hallmark pathologies, β-amyloid (Aβ) plaques and neurofibrillary tangles, but also in several other (patho-)physiological processes including immune response, neuronal growth, synaptic plasticity and energy metabolism. Although there has been recent progress in understanding APOE biology, the exact mechanisms of how APOE (especially APOE4) affects brain energy metabolism are still largely unclear. This review highlights the recent evidence of how APOE isoforms differentially affect the bioenergetic homeostasis of the brain, thereby affecting AD etiology and pathophysiology, and identifies critical questions and emerging topics that require further investigation.