Researchers seek to understand role of APOE mutation in Alzheimer's disease

If you had your genome sequenced and the report says you have the APOEε4 mutation, it does not mean you are definitely going to get Alzheimer's disease.

The reason why is complicated.

The specific genetic variant known as APOEε4 (the ε4 mutation of Apolipoprotein E) is the greatest genetic risk factor for late-onset Alzheimer's disease (AD), the most common form of AD. Inheriting APOEε4 is associated with a 15 to 20 percent increase in the likelihood of developing AD. However, the majority of people who inherit APOEε4 do not get AD, and at least 20 other genes are implicated in the disease.

AD is the sixth leading cause of death in the United States. Currently no treatments are available that prevent or slow the disease. Genetics is thought to account for up to 70% of risk for developing AD, and APOE is only one part of this heritable risk.

In the past, researchers studied the effects of APOEε4 in a few inbred mouse strains. That standardized approach is helpful in working out the molecular mechanisms of the mutation itself, but doesn't demonstrate how APOEε4 operates in different individuals with widely varying genetic backgrounds, as in the human population.

Instead, JAX scientists Michael Sasner, Gregory Carter and Gareth Howell are placing the APOEε4 mutation in mouse populations with a high level of genetic diversity, in order to sort out the complex genetic interactions involved in developing AD. The National Institute on Aging has awarded the JAX researchers a five-year grant totaling $4,191,258 million to fund this effort.

"Previous attempts to model AD in mice have utilized only a tiny fraction of the available genetic diversity," Sasner says, "and we believe this is one of the main reasons why mouse models have failed to recapitulate key aspects of human AD contributing to the lack of success in clinical trials. At JAX, we have access to mouse strains that capture as much genetic diversity as is present in the human population and the expertise to maximize their potential."

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