Apolipoprotein E4, cholinergic integrity and the pharmacogenetics of Alzheimer's disease

Recent evidence indicates that apolipoprotein E (apoE) plays a central role in the brain's response to injury. The coordinated expression of apoE and its receptors (the so-called LDL [low density lipoprotein] receptor family) appears to regulate the transport and internalization of cholesterol and phospholipids during the early phase of the re-innervation process in the adult brain. During dendritic remodelling and synaptogenesis, neurons progressively repress the synthesis of cholesterol in favour of cholesterol internalization through the apoE/LDL receptor pathway. The discovery a few years ago, that the apolipoprotein epsilon 4 allele found in 15% of the normal population 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 associated with compensatory sprouting and synaptic remodelling could be central to the AD process. The role of apoE in the central nervous system is particularly important in relation to the cholinergic system, which relies to a certain extent on the integrity of phospholipid homeostasis in neurons. Recent evidence obtained by 4 independent research teams indicates that apo epsilon 4 allele directly affects cholinergic activity in the brain of AD subjects. It was also shown to modulate the drug efficacy profile of several cholinomimetic and noncholinomimetic drugs used for the treatment of AD patients.