Almost all Alzheimer's cases arise due to APOE gene

Having specific versions of a gene known as APOE may cause most cases of Alzheimer's disease, according to a new study analysing the genetics of the disease.

Alzheimer's disease is a growing public health challenge with profound social and economic impacts. It has long been established that variations in the gene for apolipoprotein E (APOE) strongly affect Alzheimer's disease risk. We all carry two copies of the APOE gene, and there are different versions of APOE, the most common being ε2, ε3 and ε4. People carrying one or more copy of the ε4 allele have the strongest risk for developing Alzheimer's disease, followed by ε3, with ε2 conferring the least risk.

'We have long underestimated how much the APOE gene contributes to the burden of Alzheimer's disease. The ε4 variant of APOE is well recognised as harmful by dementia researchers, but much disease would not occur without the additional impact of the common ε3 allele, which has been typically misperceived as neutral in terms of Alzheimer's risk,' said Dr Dylan Williams lead researcher of the study from University College London's Division of Psychiatry and Unit for Lifelong Health and Ageing. 'When we consider the contributions of ε3 and ε4, we can see that APOE potentially has a role in almost all Alzheimer's disease.'

In the study published in npj Dementia, researchers modelled the proportion of Alzheimer's disease and dementia cases that arise due to ε3 and ε4 variants of APOE. They analysed data from nearly 470,000 participants across four large existing study cohorts and calculated the proportion of Alzheimer's disease and dementia cases that could be attributed to whether the participant carried the ε3 or ε4 variants of APOE, relative to people carrying two copies of ε2 as a low-risk baseline group.

Across the four study cohorts, the researchers found that 72-93 percent of Alzheimer's disease cases and nearly half of all-cause dementia cases would not have occurred without the ε3 or ε4 variants of APOE. This strong influence of APOE variant on Alzheimer's disease suggests that strategies which target APOE for Alzheimer's disease prevention and treatment should be prioritised.  

Yet, there are some caveats to the study's findings to consider. The study's use of the rare genotype of two copies of ε2 as the comparison group may have made the risk proportion appear larger, as most people carry ε3 or ε4.

Furthermore, carrying a risk-associated APOE variant does not mean someone will definitely develop Alzheimer's disease; it is known that lifestyle and other genetic and environmental factors still play substantial roles in Alzheimer's disease development.

Dr Sheona Scales, director of research at Alzheimer's Research UK, said: 'This study highlights that more Alzheimer's cases are linked to the APOE gene than previously thought. However, not everyone with these variants will develop Alzheimer's, demonstrating the complex relationship between genetics and other risk factors for dementia… Findings from this study show that further research into APOE will be important for developing future prevention and treatment strategies for Alzheimer's.'