Breakdown of Blood-Brain Barrier in APOE4 Carriers is Associated with Cognitive Decline

Post by Amanda McFarlan  

What's the science?

Apolipoprotein E (APOE) is a protein in the body that is important for the metabolism of fats. The E4 variant of this protein (APOE4) is known to be implicated in Alzheimer’s disease and is associated with an increased breakdown of the blood-brain barrier, a semipermeable border that controls which solutes and molecules can pass from the blood into the brain. However, it is still unknown how APOE4 contributes to the memory decline that occurs with Alzheimer’s disease. This week in Nature, Montagne and colleagues investigated the role of the APOE4 gene in blood-brain barrier breakdown and cognitive decline.

How did they do it?

The authors used dynamic contrast-enhanced magnetic resonance imaging to analyze and compare blood-brain barrier permeability in 245 cognitively normal patients who were carriers of either the APOE4 gene (associated with disease states like Alzheimer’s) or the APOE3 gene (considered to confer lower risk for Alzheimer’s). Then, the authors used positron emission tomography to investigate whether the accumulation of Aβ and tau (proteins associated with Alzheimer’s disease) in the brain contributes to the breakdown of the blood-brain barrier in APOE4 carriers compared to APOE3 carriers. They analyzed the uptake of Aβ and tau tracers in four major regions of interest: the hippocampus, the parahippocampal gyrus, the orbitofrontal cortex and the inferior temporal gyrus. Next, the authors investigated whether high levels of soluble platelet-derived growth factor receptor-β in the cerebrospinal fluid, which is known to be associated with blood-brain barrier breakdown and cognitive dysfunction, contributed to APOE4-associated blood-brain barrier permeability. They grouped patients based on whether they had high or low levels of soluble platelet-derived growth factor receptor-β in their cerebrospinal fluid. All patients received a baseline cognitive assessment that was repeated every 2 years for up to 4.5 years. Finally, the proinflammatory cyclophilin A–matrix metalloproteinase-9 pathway has been previously shown to mediate the breakdown of the blood-brain barrier in APOE4, but not APOE3, knock-in mice. Therefore, the authors explored the role of this pathway in APOE4-associated blood-brain barrier permeability and cognitive decline in humans by measuring levels of cyclophilin A and matrix metalloproteinase-9 in cerebrospinal fluid as well as cognitive impairment in APOE4 and APOE3 carriers. 

What did they find?

The authors determined that cognitively normal patients who were carriers of the APOE4 gene had higher levels of blood-brain barrier breakdown in the hippocampus and parahippocampal gyrus compared to homozygote carriers of the APOE3 gene. This permeability was shown to increase even further with cognitive impairment in APOE4 carriers, but not APOE3 carriers. APOE4 carriers also had significantly higher levels of accumulated Aβ, but not tau, in the orbital frontal cortex compared to APOE3 carriers. The orbital frontal cortex, however, did not show any evidence of increased blood-brain barrier permeability. Conversely, there was no difference in Aβ or tau levels in the hippocampus, parahippocampal gyrus, or inferior temporal gyrus between carriers of the APOE4 gene and APOE3 gene despite evidence for blood-brain barrier breakdown in APOE4 carriers. Together, these findings suggest that the breakdown of the blood-brain barrier in APOE4 carriers begins in the temporal lobe (a brain region important for memory and cognition) and is independent of Aβ and tau pathology.

Next, the authors revealed that patients with higher levels of soluble platelet-derived growth factor receptor-β in their cerebrospinal fluid at baseline showed an accelerated cognitive decline compared to patients with lower levels. Moreover, they found that higher levels of soluble platelet-derived growth factor receptor-β in APOE4 carriers, but not APOE3 carriers were a consistent predictor of cognitive decline. Finally, the authors determined that APOE4 carriers had increased levels of cyclophilin A and matrix metalloproteinase-9 that were correlated with cognitive impairment. Together, these findings suggest that the breakdown of the blood-brain barrier in carriers of the APOE4 gene contributes to cognitive decline. 

What’s the impact?

This is the first study to show that increased permeability in the blood-brain barrier in APOE4 carriers is associated with cognitive decline that occurs independently of amyloid and tau pathologies. Furthermore, the authors found that baseline levels of soluble platelet-derived growth factor receptor-β in cerebrospinal fluid could be used as a predictor of cognitive decline in APOE4 carriers. Together, these findings highlight the impact of blood-brain barrier breakdown on cognitive decline and provide insight into possible therapeutic targets that may minimize this breakdown in APOE4 carriers.

Montagne et al. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature (2020). Access the original scientific publication here.