Inheriting two copies of APOE4 linked to risk of Alzheimer’s at a younger age, study suggests

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By Alzheimer's Research UK | Monday 06 May 2024

Today, a new study was published by researchers in Spain, confirming that people who carry two copies of an Alzheimer’s risk gene, called APOE4, have a very high chance of developing Alzheimer’s disease.

These findings add to more than 30 years of research into the APOE gene, and gives researchers a new insight into how it influences a person’s risk of Alzheimer’s disease.

How do our genes affect our risk of Alzheimer’s disease?

Most cases of Alzheimer’s disease are caused by a complex mixture of factors including our age, our lifestyle and our environment – and our genes. Decades of research has revealed two different types of genes which are involved in Alzheimer’s: faulty genes, and risk genes.

Faulty genes, or mutations, that cause Alzheimer’s are rare. Someone who carries one of these rare mutations is extremely likely to develop the disease during their lifetime, often at a younger age, usually in the person’s 30s, 40s or 50s. Around one in 100 cases of dementia are caused by inherited faulty genes, and these tend to run in families. There are three main genes known to cause Alzheimer’s when faulty – APP, PSEN1 and PSEN 2.

But only rare types of Alzheimer’s disease are caused by genetics alone.

Risk genes, on the other hand, can increase (or decrease) a person’s likelihood of developing Alzheimer’s. However, even if someone carries risk genes for Alzheimer’s disease, it’s not inevitable that they will definitely develop the condition (or not) – and researchers think this is partly due to other factors like our environment and lifestyle playing a role too.

Research has identified over 75 different risk genes, many of which only have a small impact on someone’s risk. One of these, known as APOE, is by far the most important.

What is APO4?

APOE stands for apolipoprotein E. This is a protein which transports fatty molecules like cholesterol to cells in our brain. Fatty molecules are critical for cells to maintain their structure, obtain energy and to communicate with one another.

Everybody needs apolipoprotein E, and the APOE gene which carries instructions to make it, for our brain cells to work normally.

“Each of us carries two copies of APOE, one inherited from each parent” said Professor Jonathan Schott, Chief Medical Officer at Alzheimer’s Research UK. “and this means there are different combinations people can carry.”

The three most common variants are called APOE2, APOE3 and APOE4. These affect people’s risk of Alzheimer’s in different ways, with the APOE4 form having the biggest impact.

“About 1 in 50 people carry two copies of APOE4, and we have known for some time that these individuals have substantially increased risk” said Prof Jonathan Schott.

What did the new study do, and what did it find?

The study was carried out by a team of researchers based in Barcelona, Spain, supported by a range of funders including

  • Fondo de Investigaciones Sanitario,
  • Carlos III Health Institute,
  • the Centro de Investigación Biomédica en Red sobre Enfermedades
  • Neurodegenerativas and the Generalitat de Catalunya and La Caixa Foundation,
  • the US National Institute of Health,
  • the EU’s Horizon 2020
  • The US Alzheimer’s Association.

The researchers analysed medical records, including results of biomarker tests for Alzheimer’s disease, from over 10,000 people from across the US and Europe, including 519 people who carried two copies of APOE4.

They also analysed over 3,000 brain samples and accompanying medical records from people who had donated their brains to research after they died. This included 273 people who had carried two copies of APOE4.

They found that by the age of 65, nearly all APOE4 double-carriers showed abnormal levels of amyloid in their cerebrospinal fluid, a key early sign of Alzheimer’s disease, and 75% had positive amyloid scans.

And their analysis of brain tissue showed that almost all APOE4 double-carriers had signs of Alzheimer’s disease in their brains by the age of 55.

They also found that APOE4 double-carriers who developed Alzheimer’s disease symptoms did so at around 65 years of age, which is 7–10 years earlier for other APOE variants.

What does that mean for me?

As dementia is so common, many of us may have several family members affected by the condition. This does not necessarily mean that the condition is caused by a gene that runs in our family.

If you’re worried about dementia or Alzheimer’s in your family, your first port of call should be your GP. However, testing for risk genes like APOE isn’t currently recommended by, or available on, the NHS outside of clinical studies. This is because even if a test showed you carried risk genes for a disease like Alzheimer’s, you may never go on to develop symptoms of dementia, due to other factors playing a role too. And there’s no way to tell who will, or won’t, develop dementia.

There are commercial tests available for common risk genes, but these can do more psychological harm than good. As we’ve said above, other contributing factors, such as age and lifestyle, mean some people who inherit APOE4 genes still may never develop symptoms.

And when someone takes a commercial DNA test, there will be no additional support or counselling to explain what the presence of these genes means for them and their family.

If you’re worried about inherited forms of dementia that start before the age of 65, you can talk to your GP about options

Can I reduce my risk?

Every person’s risk of developing dementia is made up of lots of different factors, including our age, genes, lifestyle and environment. Evidence suggests that there are lots of things we can do to reduce our risk, regardless of whether we have inherited one or two copies APOE4.

One thing we know can be really important is to protect our brain health – and that means protecting our heart health.

For a healthy brain and heart:

  • don’t smoke
  • keep cholesterol and blood pressure under control
  • be active daily and exercise regularly
  • maintain a healthy weight
  • eat a healthy balanced diet
  • drink fewer than 14 units of alcohol per week.

If you want to find out where you can make improvements to protect your brain health, why not take our Think Brain Health check-in. https://www.alzheimersresearchuk.org/brain-health/check-in/

What are the next steps for this research?

This study shows that there is still a lot to be understood about these genes and their role in the development of Alzheimer’s disease.

Although this was a well conducted large-scale study, further research will be needed to understand how APOE4 effects a more diverse population.

The researchers looked at whether APOE4 led to people developing Alzheimer’s disease by studying a large sample of individuals who donated their brains for research. However, this group did not include people from all ethnic backgrounds.

More research will also be important to understand what other factors may interact with APOE4, as genetic and environmental factors are unique for each person.

Sitting at the heart of all of this is an unsolved mystery – it’s still not clear exactly how or why the APOE gene influences the development of Alzheimer’s diseases. Thankfully, we’re on the case. At Alzheimer’s Research UK, we are funding several research projects to try and understand how APOE can cause Alzheimer’s disease to develop and how it affects brain cells.

We hope this work, and the insights it reveals, will ultimately lead to the development of new treatments and bring us closer to a cure.

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14 Comments

  1. Claire on 7th May 2024 at 12:20 pm

    I have discovered I have 2 copies of this gene.
    I would be interested to know more about preventative measures I can take .

    Very informative reading.

    • Alzheimer's Research UK on 7th May 2024 at 1:31 pm

      Hi Claire, thanks for your question. Evidence suggests that there are lots of things we can do to help reduce our risk of developing dementia in later life, even if you have inherited two copies of the APOE4 gene. You can find out more about how to protect your brain health on our Think Brain Health hub.

  2. Rosemary on 7th May 2024 at 2:43 pm

    I’m 60 and APOE4/4 and feel devastated by these findings. What had seemed to be a ‘risk’ gene seems to be much closer now to a causative factor, given their findings of much higher penetrance of the APOE4 allele than previously thought – according to the abstract of the study similar to that for autosomal dominant Alzheimer’s or Down Syndrome. My first reaction was that I only have 5 years left as they talk about symptoms at age 65, but maybe that depends on the level of amyloid and tau pathology. I’ve seen sources before suggesting a low carb diet helps, as maintaining insulin sensitivity is important. Is that something you would concur with? I will look at your hub thanks.

    • Alzheimer's Research UK on 10th May 2024 at 5:17 pm

      Hi Rosemary, thank you for your comment. Although the chances of developing Alzheimer’s are increased with two copies of APOE4, every person’s risk of developing dementia is made up of a mixture of factors and there are things we can all do to reduce the risk, whether or not we have inherited one or two copies of APOE4 (or other genes associated with Alzheimer’s or other types of dementia). In general, what is good for our heart health is also good for brain health- this includes things like not smoking and keeping conditions like high blood pressure and diabetes under control. There is currently limited research around the topic of insulin sensitivity and dementia risk. However, research suggests that following a Mediterranean diet is the most beneficial for brain health; this is a diet rich in fresh fruits and vegetables and low in meat and dairy. You can read more about this here:
      Reducing your risk of dementia – Alzheimer’s Research UK (alzheimersresearchuk.org)

  3. Sally on 8th May 2024 at 8:04 am

    I have 1 copy of the gene (and am age 62); are there any data on my risk likelihood? Thank you

    • Alzheimer's Research UK on 13th May 2024 at 9:54 am

      Hi Sally, thanks for your comment. This study has confirmed what we previously knew – that people with one copy of APOE4 are more likely to develop Alzheimer’s disease than those without that version of the gene. Research suggests people with one copy are three times more likely to develop Alzheimer’s. However there are still ways that you can reduce your risk of developing Alzheimer’s disease, which you can read about on our website here https://www.alzheimersresearchuk.org/dementia-information/reducing-your-risk/

  4. Jo on 8th May 2024 at 10:30 pm

    Like Claire, I also have 2 copies of this gene, and at 53 years old, the findings that almost all those analysed had signs of Alzheimer’s disease in their brains by the age of 55 is somewhat terrifying. Fortunately, I have taken good care of myself, eat well and I’m very active – both mentally and physically – but who knows if that is enough. I’m a very optimistic, positive person that doesn’t scare easily, but I have to say, this information has understandably upset me – as I am sure it has others. That said, knowledge is power and prevention is better than a cure. So ultimately, I feel fortunate to have (as upsetting as it could potentially be), a head start. And yes, I know nothing is a dead cert, but these stats mean the odds do not stack well for those of us who have been unfortunate to inherited both copies of this gene.
    I have an appointment booked with my GP tomorrow to discuss this latest research and how it these genes could impact my future and what tests (if any) could be arranged going forward. I read that there is great optimism about the new (less invasive) Biomarker blood tests in development for Alzheimer’s and there are some tests already used in the US which can measure tau and amyloid proteins which can predict Alzheimers up to a decade before symptoms develop. Hopefully in the future they will be rolled out in the same way as other routine blood tests.
    In the meantime, I have just registered my interest in participating in the UK trial Blood Biomarker Challenge.

  5. Jason on 13th May 2024 at 4:39 pm

    My wife, worried about her risk of AD after her grandmother, mother and aunt all died of AD effects, took a genetic test to find out her APOE4 status. unfortunately, she has 2 copies of the gene. She is 68 and is having fairly serious cognitive issues. Are there any genetic studies involving gene therapy to try and mitigate or dampen the effects of the onset of the disease that may be caused by the APOE4 gene?

  6. Baskar on 14th May 2024 at 8:46 am

    Is the study saying that for populations of european descent with two APOE4s, the likelihood of developing Alzheimer’s is almost 100%. Additionally this is expected to happen earlier in such population relative to those with one or zero APOE4. How does this reconcile with other research which has suggested that two APOE4s have a 30-35% chance that the will develop Alzheimer’s in their lifetime. Clarity in this regard would be helpful.

    • Alzheimer's Research UK on 17th May 2024 at 10:44 am

      Hi Baskar, thanks for your comment. No, this study is not showing the likelihood is almost 100% as not everyone who has the protein, amyloid, build up in their brain, as measured in this study, goes on to develop Alzheimer’s disease. Research is ongoing to understand why this occurs. However, this study does suggest that those with two copies of APOE4 who do develop symptoms, develop them at an earlier age than those with one or zero copies of APOE4. In this study, 21% of people with two copies of the gene had an Alzheimer’s disease diagnosis, i.e., they had symptoms of Alzheimer’s, and 22% had a diagnosis of mild cognitive impairment, otherwise known as MCI. However, the researchers sought after people with symptoms so this is not an accurate representation of the number of people with symptoms in a real world population of people with two copies of the gene. Because of this, this study can’t undermine previous research showing those with two copies may be eight times more likely to develop Alzheimer’s.

  7. Karen on 17th May 2024 at 1:44 am

    Hi,
    For those of you with 2 copies of APOE4, I though I would share my dad’s story. He has two copies of APOE4 and did very well until his early 80s. Throughout his 60, 70’s and up 85 years he travelled extensively and lived a fairly normal life. As a family we noticed his memory decline in his early 80’s. He is currently in a care home (moved in last year at 86 years old). He was a smoker for at least 30 years and a heavy drinker all his life. That is the one nice thing he has forgotten. I guess my message is that it is not inevitable you will decline in your 50, 60 or even 70s. Best wishes.

  8. Anne on 17th May 2024 at 5:05 pm

    Hello,
    What scan needs to be done to see how bad the progression is if you are APOE4 homozygous?
    Thank you!
    Anne

    • Alzheimer's Research UK on 21st May 2024 at 5:57 pm

      Hi Anne, thanks for your comment. If you’re worried about symptoms of dementia, it’s best to go to your GP who can carry out some tests, like a memory test, and potentially refer you for more in-depth testing like brain scans. People aren’t usually given regular brain scans after they’ve received a diagnosis, so the focus is on monitoring how symptoms themselves are progressing.

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