Apolipoprotein E: A Novel Therapeutic Target for the Treatment of Alzheimer’s Disease

Abstract

Alzheimer disease (AD) is associated with neuronal loss, synaptic damage, deposition of beta-amyloid and loss of cholinergic activity in susceptible brain regions. The ladder three pathological markers of AD were shown to be closely associated with the presence of the apolipoprotein ε4 (apoε4) allele in sporadic AD subjects. The apoε4 allele is a well known risk factor for sporadic late onset Alzheimer’s disease; patients with two ε4 alleles exhibit an earlier age of onset, higher amyloid plaque counts, cerebrovascular amyloid, marked reductions in choline acetyltransferase and nerve growth factor receptor density as compared to non-ε4 allele subjects. Recent evidence suggest that apoE polymorphism may significantly affect the clinical presentation of the disease as well as the global efficacy of memory enhancer drugs such acetylcholine esterase inhibitors and noradrenergic modulators. Several different hypotheses have been presented to explain the effect of the ε4 allele on the age of onset and clinical progression of the disease. Because of the reported effect of low levels of apoE on synaptic plasticity, reinnervation and lipid homeostasis in apoE knockout mice, it has been proposed a little while ago that the low levels of apoE reported in brain tissues of apoε4 carriers affect lipid homeostasis in such a way that it compromises synaptic plasticity.¹