A major driver in Alzheimer’s disease

Potentially more than 90% of Alzheimer’s disease cases would not occur without the contribution of a single gene (APOE), according to a new analysis led by UCL researchers.

The scientists also found that close to half of all dementia cases would probably not arise without the gene’s influence.

The researchers say that the findings, published today in npj Dementia, highlight this gene (and the protein it produces) as a powerful yet under-recognized target for drug development, which could have the scope to prevent or treat a large proportion of all dementia.

The APOE gene has long been implicated in Alzheimer’s disease. There are three common types (alleles) of the gene, known as ε2, ε3, and ε4. Everyone carries two APOE genes, creating six different combinations of the ε2, ε3, and ε4 variants. In the 1990s, geneticists established that people carrying one or more ε4 variant face a much greater risk of Alzheimer’s than those with two copies of the more commonly inherited ε3 variant, and that groups with ε2 experience less risk relative to the ε3 carriers. 

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.

When we consider the contributions of ε3 and ε4, we can see that APOE potentially has a role in almost all Alzheimer’s disease. Consequently, if we knew how to reduce the risk that the ε3 and ε4 variants confer to people, we may be able prevent most disease from occurring.”

Dr. Dylan Williams, Lead Author, UCL Division of Psychiatry and Unit for Lifelong Health and Ageing at UCL

The study is the most comprehensive modelling to date of the proportion of Alzheimer’s and dementia cases that arise across the population due to common variation in APOE. The researchers pulled together evidence of how much the ε3 and ε4 alleles are linked to an increased risk of Alzheimer’s disease, any form of dementia, and the brain changes that lead to Alzheimer’s. Key to this study was the use of datasets from four extremely large studies (with a total of over 450,000 participants) that enabled them to find many people in the uncommon group with two copies of the ε2 variant, and use this group as a low-risk baseline in their calculations for the first time in such an analysis.

The researchers estimated that 72-93% of Alzheimer’s cases would not have occurred if it weren’t for the ε3 and ε4 alleles of the APOE gene, and approximately 45% of all dementia cases would not arise without the gene’s influence. These estimates are higher than previous estimates of APOE‘s influence, mainly because the researchers in the latest study were considering the roles of both ε3 and ε4 variants.

The variation between findings from the four studies was due to differences in how each defined and measured Alzheimer’s and dementia (including recorded diagnoses of Alzheimer’s disease or other dementias, or evidence of amyloid pathology from brain scans), as well as differences in follow-up periods and potential biases in study recruitment. Taken together, evidence from all sources suggested that APOE is most likely responsible for at least three in four Alzheimer’s cases, and possibly more.

The findings suggest the APOE gene should be prioritised in mechanistic and drug discovery research.

Dr. Williams said: “There has been major progress in recent years in gene editing and other forms of gene therapy to target genetic risk factors directly. Moreover, genetic risk also points us towards parts of our physiology that we could target with more conventional drugs. Intervening on the APOE gene specifically, or the molecular pathway between the gene and the disease, could have great, and probably under-appreciated, potential for preventing or treating a large majority of Alzheimer’s disease.

“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.”

Alzheimer’s and other dementia diseases are not caused solely by the APOE gene, as even in the rare, highest-risk category – people with two copies of ε4 – lifetime risk of Alzheimer’s disease is still estimated to be below 70%.

As Dr. Williams explained: “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. Understanding what modifies the risk people inherit from their APOE genes is another crucial question for dementia researchers to grapple with.

“For instance, other research has suggested that perhaps half of dementia incidence could be prevented or delayed by improving many modifiable risk factors such as social isolation, high cholesterol or smoking, across populations. With complex diseases like Alzheimer’s and other diseases that cause dementia, there will be more than one way to reduce disease occurrence. We should explore many options by which we might modify Alzheimer’s and dementia risk, including but not limited to strategies related to APOE.

“Nonetheless, we should not overlook the fact that without the contributions of APOE ε3 and ε4, most Alzheimer’s disease cases would not occur, irrespective of what other factors are inherited or experienced by carriers of these variants throughout life.” 

The study, conducted by researchers at UCL and the University of Eastern Finland, was supported by funding from Alzheimer’s Research UK, the Medical Research Council and others.

This study highlights that more Alzheimer’s cases are linked to the APOE gene that previously thought. However, not everyone with these variants will develop Alzheimer’s, demonstrating the complex relationship between genetics and other risk factors for dementia.

Despite APOE being linked to Alzheimer’s, very few treatments in clinical trials target this gene directly. Findings from this study show that further research into APOE will be important for developing future prevention and treatment strategies for Alzheimer’s.

Alzheimer’s Research UK is delighted to support Dr Williams as he continues to investigate how genetics alongside environmental and societal factors influence dementia risk, which will ultimately bring us closer to a cure.”

Dr. Sheona Scales, Director of Research at Alzheimer’s Research UK

Why APOE variants are linked to dementia

Previous studies have suggested that the ε4 variant might increase dementia risk because the protein it produces is less effective at clearing harmful amyloid-beta (a sticky protein that forms plaques). It also disrupts fat and energy processing in the brain cells and promotes inflammation – changes that may gradually damage neurons and make the brain more vulnerable to Alzheimer’s and related dementias. Further research is needed to confirm these mechanisms and understand why the ε3 variant increases dementia risk relative to ε2.