The Impact of Apolipoprotein E Allelic Variants on Alzheimer´s Disease

Abstract

Alzheimer disease (AD) is a genetically and clinically complex neurodegenerative disease, often with decades-long preclinical and prodromal stages. In older adults, it is the most frequent form of dementia. Apolipoprotein E (ApoE) is a lipid-transport protein whose main function is to deliver lipids to cell-surface receptors. Carriers of the APOEε4 isoform of the gene are at higher risk than APOEε3 carriers (the predominant form in the average population) of developing sporadic AD. The genetic burden of homozygous APOEε4 status together with age are the two key risk factors in the late-onset variant of AD (LOAD). APOEε4 also increases brain amyloid-β pathology relative to other ApoE isoforms and appears to influence tau pathology. The mechanisms whereby ApoE4 protein expression affects neuronal cells is far from being understood; increased aggregation and/or hampering of amyloid-β peptide clearance, microglial cell dysregulation, alteration of glutamate-mediated excitatory neurotransmission, altered modulation of amyloid precursor protein (APP), loss of acetylcholine synthesizing enzymes, disruption of neurovascular regulation, dysregulation of signal transduction cascades and various other hypotheses have been invoked. This chapter critically discusses recent advances in our knowledge of the relationship between ApoE isoforms and AD from a molecular to a clinical standpoint, and reviews current strategies for using ApoE as a diagnostic tool and a therapeutic target, respectively.