Mechanisms underlying the differential response to rosiglitazone of individuals with different ApoE genotypes

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Alzheimer?s disease (AD) is a very complex disorder for which there are few known risk factors. However it is known that advancing age increases the risk of developing AD as does possession of a particular type of a protein called apolipoprotein E (ApoE). ApoE occurs in three types (ApoE2, ApoE3, ApoE4) and possession of ApoE4 is associated with an increased risk of developing AD.One of the primary characteristic features of AD is the presence in the brain of clumps of a protein called amyloid beta-peptide (Abeta), the presence of which is thought to be detrimental to nerve cells. Abeta derives from a larger protein, called amyloid precursor protein (APP), from which Abeta is cut out. Cleavage of APP occurs primarily in the membranes of nerve cells, but in specific regions called ?lipid rafts? from where it is then exported to the outside of the cell to form the detrimental clumps containing Abeta.A drug that is used to treat diabetes (Avandia?), developed by GlaxoSmithKline, has recently been found to be useful for treating some people with AD. However, Avandia? was only beneficial for people carrying ApoE3 or ApoE2 and not ApoE4. The main functions of ApoE are to bind lipids and cholesterol and to transport them around the body. The different types of ApoE perform these functions with differing abilities but it is not known how this might relate to the differences in the observed therapeutic effects of Avandia? in AD sufferers. It is important therefore to try to understand how Avandia? is working so that better drugs can be developed.Our hypothesis is that the differential effects of Avandia? in AD patients may be related to differences in the ApoE forms that result in different (1) ability to remove Abeta from the brain or (2) sensitivity of nerve cells to the toxic effects of Abeta.Results that are of interest to the general public will be publicised on the MRC Centre for Neurodegeneration website and through reports in the associated bulletins as well as through press reports where appropriate.