Apolipoprotein E: a pharmacogenetic target for the treatment of Alzheimer's disease

The discovery that the apolipoprotein E4 (apoE4) allele is strongly linked to both sporadic and familial late-onset Alzheimer's disease (AD) raises the possibility that a dysfunction of the lipid transport system could seriously affect lipid homeostasis in the brain. We recently proposed that the abnormally low concentrations of apoE observed in the brains of apoE4 AD subjects could compromise cholesterol, fatty acid, and phospholipid transport in the central nervous system. This, in turn, would indirectly impair the cholinergic system, which, in contrast to other neurotransmitters in the central nervous system, relies heavily on lipids to synthesize acetylcholine. Several independent investigators have now confirmed the original observation of an inverse relationship between apoE4 allele copy number and residual brain choline acetyltransferase activity and nicotinic-receptor binding sites in the brains of subjects with AD. More importantly, it has been shown that the presence of the apoE4 allele differentially affects the quality and size of drug responsiveness in subjects with AD treated with cholinomimetic and noncholinomimetic agents. We also examine the role of apoE as a potent therapeutic target for AD.