There should be more focus on finding treatments that target the ‘Alzheimer’s gene’, researchers argue.
Summary
Eliminating the effect of one gene could prevent a large number of Alzheimer’s disease and dementia cases, finds research on data from nearly half a million people, including more than 170,000 UK Biobank participants. The scientists behind the work suggest that more effort should be put into finding treatments that target this gene.
One gene could play a role in at least three in four Alzheimer’s disease cases. This is according to an analysis of genetic information from nearly half a million people, including more than 170,000 UK Biobank participants.
Treatments that eliminate the gene’s effect may prevent many Alzheimer’s cases, the researchers behind the work suggest. “The advent of things like gene editing means that we have the possibility of trying to combat [gene]-related risk directly for the first time,” says study leader Dylan Williams from University College London, UK.
‘Neutral’ gene isn’t so neutral
The ‘Alzheimer’s gene’ APOE comes in three versions: ε2, ε3 and ε4. Since we all carry two copies of most genes, one from each parent, we can have one of six different APOE combinations.
What does APOE have to do with Alzheimer’s?
The APOE gene provides our cells with instructions for making apolipoprotein E, a molecule that transports fats and cholesterol around the body.
In the brain, it carries cholesterol to nerve cells. It also helps to clear up certain waste products from the brain, which form sticky clumps in the brains of people with Alzheimer’s disease.
APOE’s ε4 version seems to be less effective at this job. This, and the fact that ε4 promotes inflammation, might make the brain more vulnerable to Alzheimer’s disease.
It’s long been known that people with one or two ε4 copies face a much greater risk of developing Alzheimer’s, while having one or two ε2 copies seems to be protective. The most common situation, having one or two ε3 copies, has often been considered neutral – it neither raises nor lowers Alzheimer’s risk.
Researchers who analysed data from 470,000 people have now concluded that ε3 isn’t truly ‘risk-neutral’. “Much disease would not occur without the additional impact of the common ε3,” Williams said in a statement. For people of white European ancestry, between 72 and 93% of Alzheimer’s cases, and around 45% of dementia cases, can be linked to ε3 and ε4.
The real ‘risk baseline’ for Alzheimer’s disease would be having two copies of the protective ε2. This is only the case for around 1% of the population, so it’s crucial to look at large groups of people. “Without resources like UK Biobank, we wouldn’t be able to do this,” Williams says. “In UK Biobank, we had over a thousand individuals [with two ε2 copies].”
Treatments on the horizon
At the moment, there is only one – out of more than 100 – Alzheimer’s treatments under development that targets the gene APOE.
Alzheimer’s disease and dementia are complex conditions and whether someone will develop either is heavily influenced not just by our genes but also by our environment and behaviours. “Most people with genetic risk factors like APOE ε3 and ε4 won’t get dementia in a typical lifetime,” Williams explained.
Still, eliminating the effect of ε3 and ε4 may prevent many Alzheimer’s cases and a substantial amount of dementia cases. “Historically, the interest in APOE has not been proportionate to its importance,” Williams says. At the moment, there is only one – out of more than 100 – Alzheimer’s treatments under development that targets APOE.
Without resources like UK Biobank, we wouldn’t be able to do this.
Dr Dylan Williams, University College London, UK
The study is “a reminder of how important [APOE] is”, comments brain scientist Paul Matthews from Imperial College London, UK. But it might not be possible to eliminate APOE’s harmful effect on the brain without negatively impacting the rest of the body, where it has many important functions. “Whether it is the best target to go after is not so clear,” he points out.
Williams remains optimistic and hopes that his study will motivate other scientists to investigate APOE. “The main message is to give it the proportionate attention that it deserves in future research and funding.”
This research was covered in The Guardian, The Independent, Alzheimer’s Research UK and the Daily Mail.
This piece was corrected on 9 January 2025 to clarify the impact of environment and lifestyle on disease risk.
Related publication
- npj Dementia, January 2026
