Most Alzheimer’s cases related to gene variants

A new analysis led by researchers at University College London (United Kingdom) suggests that more than 90 percent of Alzheimer’s cases probably would not occur without the contribution of a single gene, APOE. Furthermore, about half of all dementia cases would probably not arise without the influence of this gene.

According to the researchers, the findings published in npj Dementia highlight this gene (and the protein it produces) as a powerful but little recognized objective for drug development, with the potential to prevent or treat a large proportion of all cases of dementia.

The APOE gene has been implicated in Alzheimer’s disease for a long time. There are three common types (alleles) of the geneknown as e2, e3 and e4. Each person carries two APOE genes, generating six different combinations of the e2, e3 and e4 variants. In the 1990s, geneticists determined that people who carry one or more e4 variants face much higher risk of Alzheimer’s than those with two copies of the more commonly inherited e3 variant, while groups with e2 present lower risk relative to e3 carriers.

“We have long underestimated how much the APOE gene contributes to the burden of Alzheimer’s disease. The e4 variant of APOE is recognized as harmful by dementia researchers, but much of the disease would not occur without the additional impact of the common e3 allele, which has typically been perceived as neutral in terms of Alzheimer’s risk,” said lead author Dylan Williams, from the Division of Psychiatry and Lifelong Health and Aging Unit at UCL.

“When we consider the contributions of e3 and e4, we can see that APOE could play a role in almost all cases of Alzheimer’s. Therefore, if we knew how to reduce the risk that these variants confer, we could prevent most cases,” added Williams.

The study is the most comprehensive modeling to date of the proportion of cases of Alzheimer’s and dementia that arise in the population due to common variation in APOE. Researchers gathered evidence on how much the e3 and e4 alleles are associated with an increased risk of Alzheimer’s, any form of dementia, and brain changes that lead to disease.

Additionally, key to this study was the use of data from four extremely large studies (with more than 450,000 participants in total), which made it possible to identify people with two copies of the e2 variant, a rare group, and use it as a low-risk reference in calculations for the first time in an analysis of this type.

The researchers estimated that between 72 and 93 percent of Alzheimer’s cases would not have occurred without the e3 and e4 alleles of the APOE geneand approximately 45 percent of all dementia cases would not arise without the influence of this gene. These figures are higher than previous estimates, mainly because the study considered the roles of both variants, e3 and e4.

The variation between the findings of the four studies was due to differences in how each defined and measured Alzheimer’s and dementia (recorded diagnoses or evidence of amyloid pathology through brain scans), as well as differences in follow-up periods and possible recruitment biases. Taken together, the evidence suggests that APOE is probably responsible for at least three out of four cases of Alzheimer’sand possibly more.

Priority for drug development

The findings indicate that The APOE gene should be a priority in research of mechanisms and drug development. “Intervening specifically on the APOE gene, or the molecular pathway between the gene and the disease, could have great potential, probably underestimated, to prevent or treat most cases of Alzheimer’s,” Williams said.

However, Alzheimer’s disease and other dementias are not caused solely by APOE, as even in the highest risk category – people with two copies of e4 – the lifetime risk is estimated to be below 70 percent.

“Most people with genetic risk factors such as APOE e3 and e4 will not develop dementia throughout their life, as there are complex interactions with other genetic and environmental factors. Understanding what modifies the risk that people inherit from their APOE genes is another crucial question for researchers,” Williams said.

“For example, previous studies suggest that up to half of dementia cases could be prevented or delayed by improving modifiable factors, such as social isolation, high cholesterol or smoking. With complex diseases like Alzheimer’s, there will be several ways to reduce its incidence. “We must explore multiple strategies, including, but not only, interventions related to APOE,” he added.

Even so, the researcher has stated that it should not be forgotten that without the contributions of APOE e3 and e4, most cases of Alzheimer’s would not occur, regardless of other factors inherited or experienced by carriers of these variants.