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 receptor family) appears to regulate the transport and internalization of cholesterol and phospholipids during the early phase of the reinnervation process in the adult brain. During dendritic remodelling 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 the apolipoprotein E4 allele found normal 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 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 obtained in our laboratory indicates that apo epsilon 4 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.