Researchers in Denmark have discovered why the APOE4 gene increases Alzheimer’s risk — by preventing brain cells from switching from glucose to fats for energy as they age.
The study found that as brain cells grow older and lose efficiency in using glucose — their main energy source — they can normally switch to burning lipids (fats) to survive. The APOE4 variant, however, blocks this crucial process.
Using transgenic mouse models and stem-cell-derived human brain cells, researchers found that APOE4 blocks the receptor on nerve cells responsible for lipid uptake, preventing access to this alternative fuel source.
Professor Thomas Willnow from the department of biomedicine at Aarhus University said: “The ability to use glucose diminishes in the ageing brain, forcing nerve cells to use alternative sources for energy production. Our research now documents that this alternative energy source is lipids.
“By using transgenic mouse models and stem-cell-derived human brain cell models, we uncovered that the pathway enabling nerve cells to burn lipids for energy production doesn’t work with APOE4, because this APOE variant blocks the receptor on nerve cells required for lipid uptake.”
Around 163 million people globally carry two copies of APOE4, with about 24 per cent of the world’s population carrying at least one copy.
The gene gained wider public attention when actor Chris Hemsworth revealed he carries the variant.
Willnow said: “Our research shows that the brain is highly dependent on being able to switch from glucose to lipids as we age. So those individuals who are carriers of the APOE4 gene variant – which seems to inhibit that ability – are naturally at a much higher risk.”
However, he urged carriers not to panic, noting that having the gene increases the likelihood of developing Alzheimer’s but does not make it inevitable.
“First of all, being a carrier of the gene heightens the risk but does not equal developing Alzheimer’s. One thing we can all do is live healthier.
“We know that a healthy body, to a large extent, equals a healthy brain. Although not proven in patients yet, our data also suggest that providing more healthy lipids for the cells to thrive – especially poly-unsaturated fatty acids in vegetable or fish oil – may help. Even cells that work poorly will function better when given more fuel.”
The discovery could lead to new treatment options, potentially by repurposing existing drugs that target how the body utilises lipids.
Willnow said: “Now that we know why this decrease in brain health happens, we can start to look at how to prevent or delay it.
“There are already drugs on the market that specifically target the body’s ability to utilise lipids – it might be that one of those drugs can actually be used in the treatment, or even prevention, of Alzheimer’s. I am very hopeful that might be the case.”
The team now plans proof-of-concept studies using human-derived cell models from stem cells.