Understanding the Mechanism of Action of the Major Alzheimer Gene Apolipoprotein E

This project is part of a program grant funded by the Institute of Health (NIH), involving Professor Ralph Martins' team and three other US research teams investigating other aspects of beta amyloid metabolism and accumulation.

There is strong evidence that a certain type of the Apolipoprotein E (ApoE) gene (the ε4 allele) is a strong risk factor for Alzheimer's disease (AD). It is now generally accepted that individuals possessing a single 4 allele have a 3-fold increased risk for AD, and those containing two 4 alleles have 9-fold increased risk of developing AD by 80 years of age.

The type of protein (apoE4) produced by this gene has a role of increasing beta amyloid levels in the body.

In animal studies, Professor Martins demonstrated that the presence of ApoE alters the rate of clearance of beta amyloid from two major organs known to clear this protein from the body, the liver and kidney. The research is being extended to investigate the metabolism and clearance of beta amyloid from peripheral tissues and brain in various animal models.

The results from this project will provide considerable insight into the mechanism(s) involved in beta amyloid clearance/metabolism. This may lead to the identification of ways to enhance clearance of accumulated beta amyloid within the AD brain, which may have therapeutic potential.

The animal studies have commenced and preliminary data in a small number of mice indicate that ApoE ε4 delays the clearance of the beta amyloid from the blood. The animal studies are continuing to validate these results in a larger number of animals and to determine the effect of beta amyloid metabolism and clearance from the brains and peripheral tissues of these animals.

This work will enhance our understanding as to why ApoE ε4 carriers are at such high risk of Alzheimer's disease and allow the development of effective preventive programs in this highly susceptible group that represents half the patients affected by Alzheimer's disease.