Apolipoprotein E and Alzheimer's disease: molecular mechanisms and therapeutic opportunities

Abstract

Multiple genetic and environmental factors are likely to contribute to the development of Alzheimer's disease (AD). The most important known risk factor for AD is presence of the E4 isoform of apolipoprotein E (apoE). Epidemiological studies demonstrated that apoE4 carriers have a higher risk and develop the disease and an early onset. Moreover, apoE4 is the only molecule that has been associated with all the biochemical disturbances characteristic of the disease: amyloid-beta (Abeta) deposition, tangle formation, oxidative stress, lipid homeostasis deregulation, synaptic plasticity loss and cholinergic dysfunction. This large body of evidence suggest that apoE is a key player in the pathogenesis of AD. This short review examines the current facts and hypotheses of the association between apoE4 and AD, as well as the therapeutic possibilities that apoE might offer for the treatment of this disease.

1

The Alzheimer's disease (AD) puzzle. The molecular mechanisms leading to AD have been shown to include dysfunctions in several biological processes, including oxidative stress, inflammatory responses and altered signal transduction. Aging is the major risk factor AD. Few mutations in the amy-loid precursor protein (APP) or the presenilin genes (PS) cause AD by increasing the production of Aβ. The apoE genotype is the most important genetic factor for AD. The presence of apoE4 has been associated with sever-al aspects (indicated in red) of the AD pathological cascade.

2

ApoE-based therapeutic approaches for AD. Desired therapeutic strategies would potentiate the ben-eficial effects of apoE3 (blue circle), eliminate the harmful effects of apoE4 (orange circle) or both.