Genes associated with Alzheimer Disease

Alzheimer’s disease (AD) is one of the neurodegenerative disorders, characterized by gradual loss of memory, decline in other cognitive functions and decrease in functional capacity. Increasing age and a positive family history of dementia are the defi nite risk factors of the disease. Molecular analysis of families with early onset of AD (EOAD) has made it possible to identify dominantly acting mutations in genes such as amyloid precursor protein precursor protein and presenilin 1 and 2 (PSEN 1 & PSEN 2). However, the etiology of the late onset of AD (LOAD) is less straightforward than EOAD. The availability of novel genetic tools such as high throughput methods for single nucleotide polymorphism (SNP) genotyping, which simultaneously genotype hundreds of thousands of SNPs using a single SNP array, may facilitate the discovery of genetic infl uences in the disease. These genome-wide association studies have great potential to revolutionize our ability to identify additional genes that contribute to the risk of sporadic AD. It is hoped that the identifi cation of individuals with a high genetic risk of AD will help to develop more rational, cost effective and novel prevention strategies and therapeutic approaches. INTRODUCTION Neurology Asia 2010; 15(2) : 109 – 118 Address correspondence to: Dr. Anjana Munshi, Department of Molecular Biology, Institute Of Genetics and Hospital for Genetic Diseases, Begumpet, Hyderabad-500016, India. Email: [email protected], Tel: 0091-40-27762776 Alzheimer disease (AD) is a neurodegenerative disease caused by gradual loss of memory and decrease in functional capacity. In due course of time the patient is unable to look after himself and becomes a burden on the family. AD is an age dependent disorder and its prevalence has been reported to increase with advancing age. About 10% in individuals above 65 years and 50% above 85 years of age suffer from AD. Epidemiological studies have shown that increasing age and a positive family history of dementia are the only defi nite risk factors for the disease. Having an AD–affected mother confers a greater risk than having an AD–affected father. Women are known to be at greater risk of developing AD and this has been associated with postmenopausal estrogen decline. Cardiovascular disease patients and individuals with previous head injury show higher AD risk than normal controls. A family history of AD in the fi rst degree relatives has been shown to be associated with a fourfold increase in risk in developing the disease, suggestive of a genetic involvement in AD pathogenesis. This relative risk fi gure grows higher with increasing numbers of affected fi rst-degree relatives. The characteristic features seen in the brain of AD patients are the presence of a large number of neuritic plaques, neurofi brillary tangles and cerebrovascular amyloid deposits. Neurofi brillary tangles are not specifi c to AD and therefore are not considered essential for the diagnosis. There is an extensive neuronal loss and synaptic changes in the cortex and hippocampus. Individuals with Down syndrome (trisomy 21) in general, and specifi cally with translocation (21q), are at high risk for developing AD. Down syndrome individuals with dementia have autopsy fi ndings of typical AD pathologies such as amyloid plaques and neurofi brillary tangles similar to those seen in an aging brain. GENETICS OF ALZHEIMER DISEASE AD affects around 15 million people around the world and by 2040 the fi gure is expected to rise to 80 million. The etiology entails a large genetic component. The most common form of AD (90%) in the population occurs sporadically and is late in onset, usually occurring after 65 years of age. Familial AD (FAD), or early onset AD (EOAD) REVIEW ARTICLE Neurology Asia August 2010 110 accounts for 10% of the cases and manifests itself before the age of 65 years. The mode of inheritance of AD differs in each type. Only about 10% of FAD cases are inherited in an autosomal dominant pattern. The rest of the FAD as well as LOAD cases have a non-mendelian complex mode of inheritance. Dominantly acting mutations in genes like amyloid precurssor protein (APP), presenilin -1 (PSEN1) and presenilin -2 (PSEN2) have been found to be associated with AD. These mutations have been reported to cause AD that presents early in life, often before 65 years of age (early-onset AD or EOAD). In contrast, the etiology of the late onset AD (LOAD) is less straight forward than EOAD. Although linkage approaches are diffi cult to conduct in late life disorders, there have been suggestions that contributory genes might reside on chromosomes 9q and 10q. LOAD does not seem to be the result of single gene mutations but rather the interaction of multiple genetic and environmental risk factors. Variants at only a single gene locus, the apolipoprotein E (APOE) locus on chromosome 19, have been confi rmed as modulators of susceptibility to the common late onset of AD. Risk for late-onset AD seems to be modulated by various other genetic variants with relatively low penetrance but high prevalence. Although inheritance of known genes that predispose to AD accounts for only 5-10% of all clinically presented cases the heritability for AD has been estimated to be 79%. A. GENES ASSOCIATED WITH THE LATE ONSET ALZHEIMER DISEASE 1. Apolipoprotein E (APOE) The apolipoprotein E (apoE denotes protein, APOE denotes gene) is a lipid transport protein in the brain. In humans, three different alleles Σ2, Σ3 and Σ4 exist giving rise to three common isoforms, E2, E3 and E4, with frequencies of 7%, 78% and 15% respectively. It seems that apoE has a number of roles in the central nervous system and these are being elucidated using transgenic mice. APOE has been reported to mediate neuronal protection, repair and remodeling via a number of mechanisms which include antioxidant effects, interactions with estrogen and modulation of synptodendritic proteins. APOE Σ4 allele is a major risk factor for AD and also underlies a genetic susceptibility to the effects of several forms of brain injury. Teasdale et al carried out a prospective clinical study of APOE Σ4 allele bearing patients who sustained a head injury. These individuals had a poor initial response to the injury and a poorer clinical recovery than non-APOE Σ4 individuals. A history of head injury and possession of APOE Σ4 each increase the chance of developing AD in later life by almost three fold. Σ2 allele seems to be slightly protective against AD, whereas APOE Σ3 is intermediate in risk. Having one or two APOE Σ4 alleles increases the risk of LOAD and also lowers the average age of onset with a gene dosage effect. Meta-analysis shows that the risk of AD increases by three times in heterozygotes and by 15 times in homozygotes. Undoubtedly, there is clear clinical evidence that APOE genotype has an important role to play in the pathophysiology of AD, yet the molecular mechanisms for the disease promoting effect has been diffi cult to pinpoint. It has been suggested that the formation of insoluble amyloid from soluble Aβ is promoted by APOE Σ4, which acts as a pathological chaperone. Transgenic mice with human APOE Σ4 develop a greater amyloid burden in brain in comparison with mice co-expressing APOE Σ3. However, the close relationship between APOE and Alzheimer disease risk is highlighted by the observation that transgenic mice over-expressing familial AD mutation on an APOE -/(null background) show much less amyloid deposition in comparison with those on very low to normal APOE +/+ (wild type) background. Many studies have shown that APOE Σ4 allele accounts for most of the genetic risk in sporadic AD. Thus, the contribution of other candidate genes seems to be minor. In addition to APOE tri-allele polymorphism, a genetic variant of the APOE promoter has also been proposed to be implicated in the pathogenesis of sporadic Alzheimer’s disease. Based on the data obtained from transfection assays, A/T polymorphism of the APOE promoter has been reported where the A-491 allele is associated with higher constitutive APOE promoter activity than T-491 allele.