Dementia incidence is linked to a single gene variant, according to a study

Variations in a single gene have been identified as an under-recognized target for dementia therapies.

The APOE gene has previously been identified as having a strong association with the commonest form of dementia, Alzheimer’s disease.

However, statistical modelling by the UCL team, focussing on combinations of the gene’s most common allele variants, provided further evidence of how it might impact dementias. The gene has three common allele variants – ε2, ε3, and ε4 – with all individuals carrying two APOE genes in one of six possible combinations. It was established as early as the 1990s that people with one or more 4 APOE alleles had a higher risk of developing Alzheimer's disease than people with two copies of the more common 3 allele. Likewise, ε2 carriers were at less risk compared to ε3 carriers.

Based on their modelling, the researchers estimated that 72-93% of Alzheimer’s cases would not have occurred without the presence of ε3 and ε4 alleles of the APOE gene.  They added that approximately 45% of all dementia cases would not arise without the gene’s influence.

The latest study, according to the researchers, took into account the distinct roles of both the 3 and 4 variants, which resulted in these estimates of APOE's influence that were higher than previous estimates.

Researchers studying dementia are well aware that the 4 APOE variant is harmful, but the common 3 allele, which has typically been misinterpreted as neutral in terms of Alzheimer's risk, has an additional impact that prevents many diseases. When we consider the contributions of ε3 and ε4, we can see that APOE potentially has a role in almost all Alzheimer’s disease.  As a consequence of this, we might be able to prevent the majority of diseases if we were able to reduce the risk that the 3 and 4 variants pose to individuals.

Their research published in npj Dementia, included datasets from four large studies with more than 450,000 participants, allowing a more comprehensive approach that studied the individual contribution of each of the three APOE alleles.

The scientists said the size of the study enabled them to find numerous examples from the rarer group of individuals with two ε2 alleles and for the first time to use these as their low-risk baseline. They estimated that the 3 and 4 alleles of the APOE gene would not have caused between 73% and 93% of Alzheimer's cases, and that the gene's influence would have prevented approximately 45% of dementia cases. The extent to which APOE has been researched in relation to Alzheimer’s or as a drug target has clearly not been proportionate to its full importance. He added that intervention on the APOE gene or the molecular pathway between the gene and the disease, had great potential for preventing for treating a large majority of Alzheimer’s cases.

However, he cautioned that the APOE gene should not be portrayed incorrectly as the sole cause. Even among people with two copies of the ε4 allele, the lifetime risk remained below 70%, he said.

Most people with genetic risk factors like APOE ε3 and ε4 won’t get dementia in a typical lifetime, since there are complicated interactions at play with other contributing genetic and environmental risk factors.”

Another important question for researchers studying dementia is "what modifies the risk people inherit from their APOE genes."