OVERVIEW

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 low density lipoprotein (LDL) 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 remodeling and synaptogenesis, neurons progressively repress the synthesis of cholesterol in favor of cholesterol internalization through the apoE/LDL receptor pathway. The discovery, a few years ago, that a polymorphism in the gene for ApoE (the αpoE4 allele), found normally in 15% of the general population, is strongly linked to both sporadic and familial late-onset Alzheimer's disease (AD) raised the possibility that a dysfunction of the lipid transport system, associated with compensatory sprouting and synaptic remodeling, could be central to the AD process. The role of ApoE in the central nervous system (CNS) is particularly important in relation to cholinergic system, which relies to a certain extent on the integrity of phospholipid homeostasis in neurons. Recent evidence indicates that αpoE4 allele has a direct impact on cholinergic system activity in the brain as well as on drug efficacy profile in AD subjects treated with cholinomimetic agents. Furthermore, susceptibility factors such as the gene for butyrylcholinesterase, which acts in a synergistic manner to increase the risk of developing sporadic Alzheimer's disease, were shown to modify treatment outcome significantly in patients with mild-to-moderate AD treated with noncholinergic therapies.