Large-scale UK Biobank research suggests that variations in the APOE gene, linked to up to 90% of Alzheimer’s cases, are reshaping the scientific understanding of genetic risk and highlighting APOE as the focal point for future research
New analysis of UK Biobank data supports APOE as the central genetic factor in Alzheimer’s risk. The study finds that even the common ε3 variant increases risk compared to the protective ε2, underscoring the need to target APOE in prevention and treatment research.
Given APOE’s central role, treatments that eliminate the gene’s effect may prevent many Alzheimer’s cases, the researchers 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.
Understanding APOE variants and risk
The ‘Alzheimer’s gene’ APOE comes in three versions: ε2, ε3, and ε4. Everyone carries two copies of most genes, one from each parent; therefore, we can have one of six different APOE combinations.
People with one or two copies of ε4 face a greater risk of developing Alzheimer’s, and having one or two ε2 copies appears to be protective. However, the most common situation is having one or two ε3 copies, which neither raises nor lowers Alzheimer’s risk.
Expanding on these findings, 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.
APOE variations: Shaping the landscape of Alzheimer’s research
Despite these links, Williams explained, “Most people with genetic risk factors like APOE ε3 and ε4 won’t get dementia in a typical lifetime.”
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 target APOE.
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 effects on the brain without negatively affecting the rest of the body, which 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 his study will motivate other scientists to investigate APOE. “The main message is to give it the proportionate attention it deserves in future research and funding.”
