ApoE and cerebral insulin: Trafficking, receptors, and resistance

Central nervous system (CNS) insulin resistance is associated with Alzheimer's disease (AD). In addition, the apolipoprotein E4 (apoE4) isoform is a risk factor for AD. The connection between these two factors in relation to AD is being actively explored. We summarize this literature with a focus on the transport of insulin and apoE across the blood-brain barrier (BBB) and into the CNS, the impact of apoE and insulin on the BBB, and the interactions between apoE, insulin, and the insulin receptor once present in the CNS. We highlight how CNS insulin resistance is apparent in AD and potential ways to overcome this resistance by repurposing currently approved drugs, with apoE genotype taken into consideration as the treatment response following most interventions is apoE isoform-dependent. This review is part of a special issue focusing on apoE in AD and neurodegeneration.