Expanding the association between the APOE gene and the risk of Alzheimer's disease: possible roles for APOE promoter polymorphisms and alterations in APOE transcription

Abstract

Alzheimer's disease (AD) is the most commonly diagnosed form of dementia in the elderly. Predominantly this disease is sporadic in nature with only a small percentage of patients exhibiting a familial trait. Early-onset AD may be explained by single gene defects; however, most AD cases are late onset (> 65 years) and, although there is no known definite cause for this form of the disease, there are several known risk factors. Of these, the e4 allele of the apolipoprotein E (apoE) gene (APOE) is a major risk factor. The e4 allele of APOE is one of three (e2 e3 and e4) common alleles generated by cysteine/arginine substitutions at two polymorphic sites. The possession of the e4 allele is recognized as the most common identifiable genetic risk factor for late-onset AD across most populations. Unlike the pathogenic mutations in the amyloid precursor or those in the presenilins, APOE e4 alleles increase the risk for AD but do not guarantee disease, even when present in homozygosity. In addition to the cysteine/arginine polymorphisms at the e2/e3/e4 locus, polymorphisms within the proximal promoter of the APOE gene may lead to increased apoE levels by altering transcription of the APOE gene. Here we review the genetic and biochemical evidence supporting the hypothesis that regulation of apoE protein levels may contribute to the risk of AD, distinct from the well known polymorphisms at the e2/e3/e4 locus.

An apolipoprotein E variant may protect against age‐related macular degeneration through cytokine regulation

“…In contrast to the protective role of ApoE E4 for AMD, the E4 isoform is associated with an increased risk for AD and various cardiovascular diseases [Mahley and Huang, 1999;Laws et al, 2003]. Current knowledge of the differential functioning among the ApoE isoforms, either in lipid metabolism or neuronal protection, does not readily provide a rationale for the observed protective role of E4 against AMD development [Nathan et al, 1994;Ji et al, 2002;Laws et al, 2003].…”

“…Current knowledge of the differential functioning among the ApoE isoforms, either in lipid metabolism or neuronal protection, does not readily provide a rationale for the observed protective role of E4 against AMD development [Nathan et al, 1994;Ji et al, 2002;Laws et al, 2003]. ApoE is expressed in photoreceptor outer-segments, the retinal ganglion layer, and both layers of Bruch's membrane.…”

“…7412) determine three major isoforms: E2 (112C, 158C), the most common E3 (112C, 158R), and E4 (112R, 158R). These isoforms vary greatly in terms of protein structure and function [Zannis, 1986;Jarvik, 1997;Laws et al, 2003]. The ApoE E4 isoform is correlated with elevated cholesterol concentrations and an increased risk of cardiovascular disease [Mahley and Huang, 1999;Smith, 2000;Ribalta et al, 2003].…”

“…The ApoE E4 isoform is correlated with elevated cholesterol concentrations and an increased risk of cardiovascular disease [Mahley and Huang, 1999;Smith, 2000;Ribalta et al, 2003]. The E4 isoform is also associated with various neurodegenerative diseases, most notably Alzheimer Disease (AD) [Chapman et al, 2001;Laws et al, 2003]. Cardiovascular disease, AD, and AMD share a number of similar pathological features [Klaver et al, 1998a[Klaver et al, ,1999Mullins et al, 2000;Dentchev et al, 2003].…”

Age at onset: important marker of genetic heterogeneity in Alzheimer's disease

“…In addition to and independent of the genotype-associated risk, APOE also exerts risk as a result of specific promoter polymorphisms leading to increased apoE expression. 1 However, taken together this explains less than 30% of the genetic variance of AD and we know from twin studies that other genes must be involved. Therefore, the challenge ahead of us is to devise alternate approaches which will help locate the remaining AD-associated genes.…”