If you have one copy of a gene called apoE4, then your chances of developing Alzheimer’s disease are more than doubled. Even scarier, if you carry two copies of apoE4, then you have a 12-fold risk of developing Alzheimer’s disease.
The good news is that some brilliant researchers have found a way to neutralize apoE4, albeit that the research is still in the early stages. Their work has been published in Nature Medicine.
We know that a fundamental feature of the neuropathology of Alzheimer’s disease concerns the build up of deposits of a protein called beta amyloid (Aβ), which can be neurotoxic. Aβ is regulated by apolipoprotein E (apoE), which has three common alleles (ε2, ε3, ε4) that encode three isoforms (apoE2, apoE3, apoE4). In plain language, the apoE gene has three variants that express three different types of apoE, the problematic one being apoE4.
Importantly, while humans have three alleles of apoE, most other mammals only have one allele. This difference turns out to be critical and accounts for the failure of animal studies to replicate the human situation; more on that below.
Interestingly, the isoforms of apoE (apoE2, apoE3 and apoE4) are 299-amino acid proteins that differ at only two locations, positions 112 and 158. Yadong Huang and colleagues from the Gladstone Institutes have figured out how to convert apoE4 protein into apoE3 protein. They achieved this by using gene editing to add a small molecule that corrects a structural defect in apoE4, which has the effect of transforming it into apoE3.
The most widely used animal model for studying Alzheimer’s disease is the “murine” model, based on the humble mouse. The murine model is the standard model of the illness widely used to test the potential benefits of candidate drugs. Huang and colleagues also showed that these effects do not occur in the mouse model of Alzheimer’s disease. In mice, apoE4 did not increase Aβ levels, but in humans apoE4 significantly increases Aβ levels.
In a stroke of genius, they bypassed the mouse model by using pluripotent stem cell technology to create neurons from skin samples donated by Alzheimer’s patients who were known to have two copies of the apoE4 gene. If you would like to know more about pluripotent stem cells, head on over to the Allen Cell Explorer.