Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease

Abstract

An increased risk for Alzheimer's disease is associated with dyslipidemia and insulin resistance. A separate literature shows the genetic risk for developing Alzheimer's disease is strongly correlated to the presence of the E4 isoform of the apolipoprotein E carrier protein. Understanding how apolipoprotein E carrier protein, lipids, amyloid β peptides, glucose, central nervous system insulin, and peripheral insulin interact with one another in Alzheimer's disease is an area of increasing interest. Here, we will review the evidence relating apolipoprotein E carrier protein, lipids, and insulin action to Alzheimer's disease and Aβ peptides and then propose mechanisms as to how these factors might interact with one another to impair cognition and promote Alzheimer's disease.

Keywords: Alzheimer's disease; apolipoprotein E; cognition; dyslipidemia; insulin resistance.

Figure 1

Schematic of metabolic factors involved in E4 status and cognitive impairment. (a) In the healthy state, insulin (green arrow) and FFA (curvy arrow) cross into the brain at a normal rate. In brain, FFA are incorporated into APOE, and APOE assists in clearing Aβ, via BBB transporters such as LRP1 (yellow arrow). Perhaps by modulating these mechanisms, brain insulin promotes cognitive health. (b) Both peripheral and central insulin resistance (IR) are associated with AD. Peripheral IR is associated with inflammation, elevated triglyceride levels, and obesity and the latter with decreased transport of insulin across the BBB. Dyslipidemia can exacerbate IR and vice versa in a vicious cycle. Central IR and elevated triglyceride levels are associated with cognitive impairments. Inflammation decreases the clearance of Aβ by LRP-1 and could contribute to formation of Aβ plaques. (c) The APOE4 protein isoform binds lipids less well and E4 carriers with AD have decreased levels of brain insulin. These variances in E4 carriers could lead to interference with Aβ binding, resulting in decreased clearance from the CNS and an increased Aβ burden compared to E4 non-carriers. Because these relationships among insulin, triglyceride, and amyloid clearance in the E4 state are speculations, they are marked with a “?”