One Gene Influences 75 Percent of Alzheimer’s Disease Cases

Alzheimer’s disease, the most common cause of dementia, has complex genetic and environmental causes. A new study that combined data from four large analyses of the disease has suggested that one single gene may influence as many as nine out of ten cases.¹

Identifying Harmful Gene Variants

Scientists have linked the APOE gene, which codes for a protein that carries cholesterol in the bloodstream, to Alzheimer’s disease since the 1990s, but the new data suggest that the field has underestimated the gene’s impact.

The APOE gene has three common alleles known as ε2, ε3, and ε4. The highest risk allele combination is ε4/ε4, as people with these variants have a 70 percent chance of developing Alzheimer’s disease.²

“The ε4 variant of APOE is well recognized 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 Dylan Williams, an epidemiologist at University College London and coauthor of the new paper, in a statement. “When we consider the contributions of ε3 and ε4, we can see that APOE potentially has a role in almost all Alzheimer’s disease,” he added.

Recruiting Those at the Least Risk of Alzheimer’s Disease

Previous studies have shown that people carrying ε3 variants have a lower risk of disease than those with ε4. People carrying ε2 variants have the lowest risk. Because the ε2 allele is so rare—99 percent of the population carries the ε3 and ε4 alleles—scientists have struggled to recruit enough people with the variant in their studies. In the new study, which included data from 450,000 people, the researchers were able to recruit these individuals and used them as a baseline for their analysis.

Williams and his team showed that the ε3 and ε4 variants together caused between 72 and 93 percent of Alzheimer’s disease cases and roughly 45 percent of all-cause dementia cases.

The researchers said that their study findings should encourage the field to reframe the importance of APOE in research to identify the mechanisms of Alzheimer’s disease and potential drug targets for the disorder. “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,” said Williams.

Researchers think that the ε4 variant of APOE is less able to clear the brain of harmful amyloid protein, which can form thick plaques. This variant may also cause inflammation and disrupted metabolism in affected brains. How disease risk is affected in ε3 variant carriers relative to those with the ε2 variant is unclear, as many previous studies combined the two variants, the authors wrote.

Further research is also needed to fully understand how APOE gene variants interact with other risk factors. Most people with genetic risk factors, such as ε3 and ε4 variants, will remain disease-free over a normal lifespan. Williams said that the field needs to study APOE in this complicated context. “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,” said Williams.

“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,” he concluded.