Apolipoprotein E and lipid homeostasis in the etiology and treatment of sporadic Alzheimer’s disease

The discovery that the apolipoprotein E (apoE) e4 allele is genetically linked to both sporadic and familiallate-onset Alzheimer’s disease (AD) raises the possibility that a dysfunction of the lipid transport systemcould seriously affect lipid homeostasis in the brain of AD subjects. The presence of the e4 allele has beenassociated with lower levels of apoE in both serum and brain tissues of normal and AD subjects. In anattempt to reverse the apoE deficit in AD, we identified and characterized several apoE inducer agentsusing a low-throughput in vitro screening assay. The most promising of these compounds is calledprobucol. Administration of probucol, an old cholesterol-lowering drug, in a pilot trial in mild-to-moderate sporadic AD led to a significant increase in cerebrospinal fluid (CSF) apoE levels and adecrease in CSF in both phosphorylated tau 181 and beta-amyloid 1e42 concentrations without sig-nificant modifications of lipid hydroperoxide levels. 2014 Elsevier Inc. All rights reserved.