One of the more vexing problems bedeviling Alzheimer’s research is why so many treatments that are successful in mouse models fail in clinical trials with humans. In a paper published yesterday in Nature Medicine, a team of researchers at the Gladstone Institutes identified how a key genetic variant associated with the development of Alzheimer’s operates differently in mice and humans. They also showed that the problematic gene can be repaired.
The gene apolipoprotein E3 (ApoE3) has a variant called ApoE4 that is strongly associated with the development of Alzheimer’s Disease. Individuals with one copy of the ApoE4 gene are twice as likely to develop Alzheimer’s compared to those with ApoE3. Those with two copies of ApoE4 are twelve times more likely to develop the disease.
The two ApoE genes create their own forms of an ApoE protein. The ApoE4 protein is broken into fragments because it can’t fulfill the normal functions of the ApoE3 protein in human nerve cells. The creation of the fragments is associated with increased production of amyloid-β peptides and increased levels of tau phosphorylation. Both of these factors are strongly associated with Alzheimer’s.
How ApoE4 is linked to Alzheimer’s in humans and mice
There are three possible explanations for how the ApoE4 gene may contribute to Alzheimer’s Disease. The toxic effects of the increases in amyloid-β and tau phosphorylation from the breakdown of the ApoE4 protein could be the culprit. It’s also possible that the absence of ApoE3 (because it was replaced by ApoE4) could be the problem. Finally, it could be a combination of both factors.
The researchers untangled these three possibilities by looking at the effect of ApoE3 and ApoE4 on human nerve cells. Neurons were developed from pluripotent stem cells (stem cells that can develop into any type of cell) taken from volunteers who either had two copies of the ApoE3 gene or two copies of the ApoE4 variant.
They compared the ApoE3 and ApoE4 neurons with neurons that didn’t produce either type of ApoE protein. They found that the neurons that produced no ApoE protein functioned like the neurons that produced ApoE3. They concluded that the link between the ApoE4 gene and Alzheimer’s stems from the toxic effects associated with ApoE4 and not from the absence of ApoE3. This finding also rules out the possibility that both factors contribute to the development of Alzheimer’s.
The finding that breakdown of the ApoE4 protein is associated with Alzheimer’s also provides insight into why treatments that work with mice may fail with humans. Amyloid-β production is not affected by the ApoE4 gene in mice. Treatments that have been shown to be effective with mice may not be as successful with humans because the mouse models don’t address ApoE4-related forms of Alzheimer’s in humans.
Differences in how ApoE4 functions in mice and humans isn’t the whole story, however, because treatments for Alzheimer’s that focus on reducing amyloid-β have been successful in mice. However, it does point to a clear difference between humans and mice with regard to Alzheimer’s that can serve as a focus for future research.
Negating the effects of ApoE4
The finding that the toxic effects of the ApoE4 protein are associated with Alzheimer’s in humans suggests treatment methods might be successful if they focused on modifying the ApoE4 protein before it‘s broken down into the problem-causing fragments.
The researchers took a different approach. Rather than trying to counter the effects of the ApoE4 protein, they eliminated its effects by converting ApoE4 to ApoE3 using gene editing techniques. The converted genes did not produce the ApoE4 protein which is the root cause of the problem.
Finding a solution for Alzheimer’s Disease has proven to be difficult. New research findings that appear promising at first but don’t provide the answers we’re looking for are frustrating for everyone and heart-breaking for families devastated by Alzheimer’s.
Nevertheless, so much has been learned about Alzheimer’s that it’s hard to avoid the conclusion that we’re getting closer to finding effective treatments. The research reported in Nature Medicine appears to have illuminated additional pieces in the Alzheimer’s puzzle and opened up new approaches to finding a cure. Progress is slower than anyone likes, but it is being made and there’s hope for the future.
Kevin Murnane covers science, technology and video games for Forbes. His blogs are The Info Monkey & Tuned In To Cycling and he's The Info Monkey on Facebook & @TheInfoMonkey on Twitter.