Solving a 30-year mystery – how an important Alzheimer’s risk gene affects our brain

Lots of factors affect a person’s risk of getting Alzheimer’s disease, the number one cause of dementia. It’s a complex mix of lifestyle, health and age, but our genetic makeup plays a particularly important role in determining whether we will get Alzheimer’s.

There are many genes in our DNA that, in combination, can increase our risk of Alzheimer’s- but there are variations in  one gene in particular which seems to have the biggest influence.

This gene, called APOE, was first linked to late-onset Alzheimer’s in 1993. Since then, researchers have been trying to understand the reasons why this gene is so strongly linked to Alzheimer’s.

In 2022, Thor actor Chris Hemsworth revealed in his National Geographic docuseries Limitless that he has a version of the APOE gene that makes him more likely to develop Alzheimer’s.

In an interview with Vanity Fair, Mr Hemsworth gave more details on his discovery, stressing that whilst having the risk gene does significantly increase his chances of getting Alzheimer’s, it is not a diagnosis –  there is no guarantee he will get the disease.

But what exactly is this APOE gene? And what is its role in Alzheimer’s?

Researchers, at last, may be closer to the answer.

Late last year, a team based at Massachusetts Institute of Technology (MIT) in the US published new discoveries about the APOE gene in the scientific journal, Nature.

What they found reveals new clues as to how different versions of the gene causes changes in the brain, which scientists have been trying to understand for the past 30 years. These new findings could finally explain why some versions of the APOE gene – known as ‘variants’ – increase our risk of Alzheimer’s.

First, what is the APOE gene and why does it matter?

“APOE stands for apolipoprotein E” explains Dr HK Irundika Dias, who studies APOE in an Alzheimer’s Research UK-funded project at Aston University. “This is a protein which delivers fatty molecules like cholesterol to cells in our brain.”

You might have heard of cholesterol in the context of heart health, with so-called ‘bad cholesterol’ increasing our risk of heart disease.

But cholesterol isn’t all bad –  in fact, all our cells, including brain cells, need fats like cholesterol to function properly. This is because fatty molecules are critical for cells to maintain their structure, obtain energy and to communicate with one another. “Therefore, we need apolipoprotein E, and the APOE gene which contains instructions to make it, in order for our brain cells to work normally.” says Dr Dias.

We each have two copies of the APOE gene in our cells’ DNA – one copy inherited from each of our parents. To complicate things, there are different variants of APOE found in people around the world – the three most common are called APOE2, APOE3 and APOE4.

“They are essentially the same protein,” says Dr Dias. “But each variant has tiny differences in 3D structure.

“And in biology, even a small change can affect how the protein works in the brain.”

The last of these, APOE4, is most strongly linked to Alzheimer’s disease.

And since we can inherit different combinations of APOE variants from our parents, some people can inherit two copies of the APOE4 variant.

Around one in four people carry a single copy of the APOE4 variant – these individuals are around three times more likely to develop Alzheimer’s disease in later life compared to people without this variant. And for people who carry two copies of APOE4 (which is the case for around one in fifty of us – including actor Chris Hemsworth), the lifetime risk more than doubles compared to having just one copy.

But why?

APOE4, cholesterol and cognitive decline

Dr Dias outlines the science and thinking behind the new findings:“For decades, scientists have been trying to connect the dots between the APOE4 variant, changes in the way cholesterol is distributed around brain cells, and how this could lead to Alzheimer’s symptoms like memory decline. So far, the links between these have been unclear.”

Finally, the team from MIT might have some of the answers.

To identify differences between people who carry the APOE4 variant and people who don’t, the researchers analysed brains donated from people who had died. They also used stem cells donated from people to grow human brain cells in the lab, so they could better understand how APOE4 affects living brain cells.

They found important, never-before-observed differences in the brain cells of APOE4 carriers.

Firstly, the team studied specialised brain cells called oligodendrocytes. These are cells that make a fatty substance called myelin, which acts as a protective coating for nerve cells (a bit like the plastic around electrical wires) and ensures the nerve cells can transmit electrical impulses properly.

Looking under the microscope, the team found unusual piles of cholesterol inside these oligodendrocytes which had the APOE4 variant. The team think this could be due to  the APOE4 variant changing how cholesterol is transported around the cell.

Secondly, the researchers found that nerve cells from people with the APOE4 variant had less of the protective myelin coating compared to cells from people with the APOE3 variant.

“These findings are very exciting,” says Dr Dias. “The researchers have approached the study from many angles and have shown how APOE4 affects both oligodendrocytes and nerve  cells in the brain.”

Taking their findings one step further, the MIT team also tested a cholesterol-binding chemical called cyclodextrin, which makes cholesterol more soluble and easier to transport. They gave this chemical to mice carrying the APOE4 variant to see if they could boost cholesterol transport and myelin production, which appear to be disrupted in APOE4 oligodendrocytes.

What they found was very promising – not only did the chemical improve how the mouse brain cells process fat, but it also improved the mice’s performance in memory and thinking tests.

“Researchers are still a long way from testing this in people” Dr Dias says, “But the fact we can use these technologies to look for potential drugs that limit the effects of APOE4 is a promising part  of the study.”

A milestone for understanding Alzheimer’s risk?

Dr Dias says that these results open many more avenues for future research.

“There are obviously many factors that influence a person’s risk of Alzheimer’s, and APOE4 is just a part of that puzzle,” Dr Dias points out. “But the researchers in this study have shed light on how APOE4 affects our brain. It is what researchers studying APOE all these years have been waiting for.”

Dr Rosa Sancho, Alzheimer’s Research UK’s Head of Research, is often asked by the media for her opinion  on new research into dementia risk factors.

“Alzheimer’s risk is complicated” says Dr Sancho. “Or at least, an individual’s risk of Alzheimer’s is complicated. Genes are one part of the puzzle. In fact, over 70 genes are linked to Alzheimer’s risk. but there are other important things too – such as our lifestyles and age.”

And, says Dr Sancho, our genetics also interact with our lifestyle in complicated and unpredictable ways.

“It’s important to remember that carrying one or two copies of the APOE4 variant doesn’t automatically guarantee that a person will definitely get Alzheimer’s. We know that some people with APOE4 never go on to develop the disease.”

“We cannot control what genes we inherit, but research shows there are things we can do to reduce our risk of developing diseases like Alzheimer’s that go on to cause dementia,” Dr Sancho says. “Whether it be eating more healthy meals or taking a brisk walk at lunchtime, or perhaps taking up a new hobby – there are plenty of ways that we can actively reduce our risk of Alzheimer’s, regardless of what APOE genes we have.”

For many researchers, including Dr Dias, this new study is a milestone when it comes to understanding the link between APOE4 and our brain. Without a doubt, it will pave the way for future studies exploring more biological mechanisms that underpin Alzheimer’s disease, which is essential if we are to understand disease risk and – perhaps – find a cure.

Should we be worried about APOE4?

By sharing his APOE status, Chris Hemsworth is raising awareness of this  element of Alzheimer’s risk. It is important to remember that this gene is just one piece of a complex puzzle that determines each individual’s risk of the disease.

Given the uncertainty over whether someone with APOE4 will develop Alzheimer’s, the NHS doesn’t routinely offer tests for APOE genes. If you’re worried or interested in learning more about genes and dementia, our has more information and you can contact our Dementia Research Infoline.

And no matter what genetic hand you have been dealt, Alzheimer’s Research UK’s Think Brain Health campaign has more information on the positive steps we can all take to look after our brain health, and reduce our risk of dementia.