Most cases of Alzheimer’s disease are associated with variations in a single gene

APOE has long been known as one of the key genetic risk factors for Alzheimer’s disease. It exists in three main variants — e2, e3, and e4— and each person carries two copies of the gene, forming one of six possible combinations. Previously, it was believed that the e4 variant makes the main contribution to the development of the disease, while the most common e3 was perceived as relatively neutral.

However, a new study shows that this estimate was underestimated. According to the lead author of the study, Dr. Dylan Williams, the contribution of APOE to the overall burden of Alzheimer’s disease has long been underestimated. Taking into account the influence of not only e4, but also e3 demonstrates that APOE can play a role in almost all cases of the disease.

The study was the most comprehensive simulation of the contribution of APOE to the development of Alzheimer’s disease and dementia at the population level. The researchers combined data from four large cohort studies involving more than 450,000 people. This made it possible for the first time to use a rare group of people with two copies of the protective variant e2 as a minimum risk standard.

Based on these data, the researchers estimated that 72 to 93% of Alzheimer’s cases would not have occurred without the influence of variants e3 and e4 of the APOE gene. For all forms of dementia, this proportion is about 45%. The spread of estimates is explained by differences in diagnostic methods, duration of observations, and criteria for inclusion of participants in different studies.

The results significantly enhance previous assessments of the role of APOE and emphasize its importance as a promising target for drug development. According to the authors, interfering with the work of the gene itself or with the molecular pathways linking APOE to pathological changes in the brain may make it possible to prevent or slow down the development of most cases of Alzheimer’s disease.

At the same time, the researchers emphasize that APOE is not the only cause of dementia. Even people with the highest genetic risk — carriers of two copies of e4 — are less than 70% likely to develop Alzheimer’s disease during their lifetime. This indicates a complex interaction of genetic, environmental, and behavioral factors.

It is noted that modifiable risk factors such as social isolation, smoking, or high cholesterol still play an important role and can significantly reduce the incidence of dementia at the population level. Nevertheless, the contribution of APOE remains fundamental: without the influence of its variants, most cases of Alzheimer’s disease would probably not have occurred.

The study was conducted by scientists from UCL and the University of Eastern Finland and highlights the need to re-prioritize the development of preventive and therapeutic strategies to combat dementia.