Association between Alzheimer's Disease and Apolipoprotein E Polymorphisms

Article excerpt

Abstract

Background: Alzheimer's disease as a neurodegenerative disorder is the commonest type of dementia. A growing number of genes have been reported as the risk factors, which increase the susceptibility to Alzheimer's disease. Apolipoprotein E (APOE), which its ε4 allele has been reported as a risk factor in late onset Alzheimer's disease (AD), is the main cholesterol carrier in the brain. The main goal of this study was to assess the role of APOE genotypes and alleles in AD in Iranian population.

Methods: This study was performed in Tehran, Iran from 2007 to 2008. Totally, 154 AD cases and 162 control subjects from Iranian population were genotyped for APOE using PCR method. Genotype and alleles frequencies for APOE were calculated and compared between AD case and control subjects by γ2 or Fisher's exact test. Type one error assumed less than 0.05.

Results: The frequency of ε2ε3 genotype was significantly higher in control subjects than AD patients was (13.5% versus 5.2%, P< 0.05) and ε3ε4 genotype frequency was significantly higher in AD cases compared with control subjects. APOE -ε2 allele frequency in cases was lower than that of control subjects but this difference was not significant (4.2% versus 7.7%).

Conclusion: It seems that individuals carrying ε4 allele, develop AD 6.5 times more than non-carriers do (OR= 6.566, 95% CI= 2.89-14.92). It has been reported that ε4 allele acts in dose- age-dependent manner but we have shown that the risk of developing AD in male APOE -ε4 allele carriers is higher than that of female ε4 carriers.

Keywords: Alzheimer' Disease, Apolipoprotein E, Iran

Introduction

Alzheimer's disease (AD), which presents progressive cognitive defects such as memory loss, apraxia and personality changes, is the commonest cause of dementia in the mid and late ages (1, 2). Two neuropathophysiological hallmarks of AD are intracellular neurofibrillary tangles and beta amyloid plaques in brain blood vessels. As hundreds genes have been known as the risk factors for late onset AD, the well-known one is apolipoprotein E gene (APOE) which has been recognized as the most important risk factor in 65% of sporadic cases (3).

Apolipoprotein E is the main part of very lowdensity lipoproteins, Intermediate density lipoproteins (IDL), chilomicrons and the main cholesterol carrier in the brain and its synthesis is independent in central nervous system (CNS) and lung. As APOE expression is stimulated by any CNS damages or diseases, it seems that APOE regulates cholesterol metabolism and distribution in the brain to repair and stabilize neurons' membrane and myelin (4-6). Apolipoprotein E isoforms, which coded by ε2, ε3 and ε4 alleles, are only different in two amino acids of 112th and 158th; ε2 (Cys 112, Cys158), ε3 (Cys112, Arg158) and ε4 (Arg 112, Arg158).

APOE-ε4 allele has been identified as a genetic susceptibility factor for AD in various populations. This allele increases the risk of late onset AD and lowers the onset age in a dose-dependent manner (7-11).

This study has been focused on the distribution of APOE genotypes and allele frequencies and the association of APOE alleles with AD in Iranian population. Raygani et al. showed that APOE- ε4 allele was a risk factor in developing AD in Iranian population but the protective role for APOE- ε2 against AD in this population was not statistically significant (8).

We aimed to perform a study with a bigger sample size and more considerations were taken into account about potential confounders.

Material and Methods

This case and control study involved 154 AD cases (with mean age of 78.55±7.80 yr) and 162 control subjects (with mean age of 77.14±6.95 yr) in which AD cases and control subjects were included if they were older than 65 yr old and the informed consent was signed by them or their legal guardians. The criterion for inclusion as a case was the diagnosis of AD diagnosed by an expert psychiatrist based on DSM IV criteria and lacking any neurologic or psychiatric disorders for control group according to medical report or responsible physician's statements. …