Most Alzheimer’s cases linked to a single gene, study finds

Researchers found that nine out of 10 cases of Alzheimer’s disease would not develop without the contribution of a single gene, and almost half of cases of dementia would not develop either.

Alzheimer’s is the most common form of dementia, accounting for 60 to 80 per cent of almost a million cases of dementia in the UK.

A complex set of factors, including age, lifestyle choices such as smoking, and environmental factors such as air pollution and genes, can all contribute to the risk of developing Alzheimer’s disease.

A gene called APOE has long been known to increase the risk of Alzheimer’s disease.

But scientists have found that without a particular variant of this gene, most cases would not occur, making it a strong target for drug development, according to researchers at University College London (UCL) and the University of Eastern Finland.

Everyone carries two APOE genes, with three common types of the gene known as ε2, ε3 and ε4. Previous studies suggested that the ε4 variant may increase the risk of dementia because the protein it produces is less effective at clearing harmful amyloid-beta, a sticky protein that forms plaques between brain cells and eventually leads to cognitive decline.

Lead author Dr. Dylan Williams said: “We have long underestimated how much the APOE gene contributes to the burden of Alzheimer’s disease. The ε4 variant of APOE is considered deleterious by dementia researchers, but many diseases would not occur without the additional effect of the common ε3 allele (variant), which is generally perceived as neutral in terms of Alzheimer’s risk.”

“When we consider the contributions of ε3 and ε4, we can see that APOE could potentially play a role in almost all Alzheimer’s diseases. Ultimately, if we knew how to reduce the risk that ε3 and ε4 variants pose to humans, we could prevent most diseases from occurring.”

In the 1990s, geneticists found that people carrying one or more ε4 variants faced a much greater risk of Alzheimer’s than those with two copies of the more commonly inherited ε3 variant, and groups with ε2 experienced less risk than ε3 carriers.

But this latest study suggests that most cases of Alzheimer’s and dementia would not occur without the ε3 variant.

For the study published in the journal npj DementiaUsing databases from four large studies totaling 450,000 participants, researchers pieced together evidence on how ε3 and ε4 variants are linked to increased risk of Alzheimer’s disease, any type of dementia, and brain changes that lead to Alzheimer’s.

Using the data, researchers estimated that 72 to 93 percent of Alzheimer’s cases would not occur without the ε3 and ε4 variants of the APOE gene, and about 45 percent of all dementia cases would not occur without the gene’s influence.

Although Alzheimer’s and other dementing diseases are not caused solely by the APOE gene, and many people with these genetic risk factors typically do not develop dementia in their lifetime, understanding the risk provides “the potential to prevent or treat the vast majority of Alzheimer’s disease,” Mr. Williams explained.

Alzheimer’s Research UK research director Dr. Sheona Scales said: “This study highlights that more cases of Alzheimer’s than previously thought are linked to the APOE gene. But not everyone with these variants will develop Alzheimer’s, highlighting the complex relationship between genetics and other risk factors for dementia.”

“Despite APOE being linked to Alzheimer’s, few treatments in clinical trials directly target this gene. The findings from this study suggest that further research into APOE will be important to develop future prevention and treatment strategies for Alzheimer’s.”

Masud Husain, professor of neurology at the University of Oxford, said: “This is a really important study. It reveals how important different variants of the APOE gene are in influencing the risk of developing Alzheimer’s disease. But it also raises the question of whether it would be useful to know your APOE genotype. Currently this is not routinely available on the NHS.”

“This is largely because it is unclear what someone can do if they find they are at high risk of developing dementia. We absolutely need clinical trials focused on these high-risk people to determine whether new treatments can make a difference for them.”