The Genetics Of Susceptibility To Alzheimer's Disease

The Genetics of susceptibility to Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia affecting over 417 thousand people in the UKii, over 5 million people in the USA and over 26 million people worldwideiii. There are two forms of Alzheimer's disease; familial Alzheimer's disease (FAD) and sporadic Alzheimer's disease which can be further subdivided into early onset Alzheimer's disease (EOAD) and late onset Alzheimer's disease (LOAD). Late onset Alzheimer's in the most common form and generally affects those who are aged 65 or over whilst early onset Alzheimer's can occur in people at a much younger age.iv According to the NHS dementia is "a syndrome ([or]a group of related symptoms) that [are] associated with an ongoing decline of the brain and its abilities." Symptoms of dementia may include loss of cognitive ability, communicative skill and motor functions.v Alzheimer's is generally acknowledged to be caused by the degeneration of brain neurons which can be attributed in part to a build up of Amyloid plaquesvi . Despite the prevalence and public awareness of Alzheimer's however, an effective cure has not yet been discovered, nor is the relationship between Amyloid plaque build up and neurone degeneration fully understood. With no definite cure in sight, those who suffer from Alzheimer's rely on symptomatic therapies that help to relieve the effects of the disease. Although no cure has yet been discovered for Alzheimer's there is strong research evidence to suggest that the disease has a genetic basis and two recent genome wide association studies (GWAS) discovered three new susceptibility loci for late onset Alzheimer's disease. It is hoped that recent research findings, in addition to the currently known factors that contribute to Alzheimer's disease, will lead to an effective treatment soon being developed. As less than 1% of reported AD cases are a result of familial inheritance there remains a strong hope that AD can be almost fully eradicated. It is the aim of this essay to provide an overview of recent LOAD research findings, discuss the research techniques used and investigate the genetic basis for susceptibility to Alzheimer's. One of the most important discoveries in Alzheimer's research was made by Corder et al in 1993. It was Corder who first reported the association between the ?4 allele of apolipoprotein E (APOE) and the development of LOAD.vii The APOE gene is found on chromosome 19 in the human cell and has several different alleles with ?2, ?3 and ?4 being the most common forms.viii APOE is a protein that binds to lipids and forms lipoproteins that transport dietary fat's through the blood streamix. Research studies by Qiang Liu et al (2007) have shown a direct biological relationship between APP (Amyloid precursor protein, the precursor to amyloid-?) and APOE.x Whilst the ?2 and ?3 alleles pose no risk of LOAD being developed, the presence of either 1 or 2 ?4 alleles in a chromosome does significantly increase the chance of a person developing LOAD, with APOE being said to account for "up to 50% of the genetic risk for AD"xi. Having the ?4 allele does not mean that there is a 100% chance of Alzheimer's being developed though as some people carrying two ?4 alleles do not develop Alzheimer'sxii. This suggests that there are multiple genetic factors that contribute to the development of Alzheimer's. Whilst Corder et al's study supports the hypothesis that LOAD is caused by the overproduction and build up of A? (through the ?4 allele of APOE) in the brain, research conducted by Lambert et al and Harold et al highlights another set of genetic factors that almost certainly contribute to the development of LOAD. Both Harold et al and Lambert et al conducted genome-wide association studies (GWAS) in order to identify other risk loci for Alzheimer's. A genome-wide association study is a powerful method in genetic research that involves "...rapidly scanning markers across the complete sets of DNA, or genomes, of many people to find genetic variations associated with a particular disease."xiii The genetic markers used by both Harold and Lambert were single nucleotide polymorphisms (single base pair changes in a DNA strand). These markers represent variations in genes and can be counted on a large scale in order to ascertain whether a certain genetic variation is associated with a disease, i.e. if a high percentage of people suffering from disease X also have variation P then it can be inferred that variation P is associated with the development of disease X. GWAS can be seen to be a lot stronger than previous genetic approaches such as reverse genetics as no phenotype needs to be observed in order for a gene to be identified. As no directly observable evidence is needed, gene-effect correlations can be drawn a lot more easily and quickly, thus allowing information to be gathered at a faster rate and beneficial medical research to take place earlier. The study conducted by Harold et al was the "most powerful AD GWAS xiv [to be conducted] to date". The experiment was divided into two stages, in stage one the APOE association experiment conducted by Corder et al was replicated however two new loci SNP's were observed that had not been previously associated with AD. A further GWAS was conducted and it was concluded that the CLU gene (also known as APOJ) and a loci at 5' to the PICALM gene could also be associated with late onset Alzheimer's disease.xv Lambert et al also conducted a GWAS using SNP markers outside APOE that had, from previous research, been suggested to have evidence of association with AD. The two loci that gave replicated evidence of association with AD were CLU (APOJ) and CR1.xvi Between the two studies three new associated variants were discovered, CLU, CR1 and PICALM (though it should be noted that evidence for the association of CLU was gathered by both GWAS increasing the reliability of the theory that CLU is associated with AD). CLU is a gene located on chromosome 8 that codes for the protein Clusterin (also known as apolipoprotein J). Clusterin is associated with the clearance of cell debris and the process of apoptosis (cell death).xvii CR1 is a gene located on chromosome 1 that codes for a single pass type glycoprotein and mediates cellular binding to particles and immune complexes that have activated compliment.xviii Previous biological studies also "support the roles of CLU and CR1 in the clearance of ? amyloid"xix from the brain. PICALM is a gene located on chromosome 11. It is an assembly protein that "may be required to determine the amount of [cell] membrane to be recycled" and may also be "involved in endocytosis at the neuromuscular junction."xx PICALM is also thought to be associated with the removal of ? amyloid from the brain through "APP processing via endocytic pathways, resulting in changes in A? levels."xxi As well as the possible effect PICALM might have on A? it is also possible that PICALM might directly affect the brain synapses. In the 2009 letter written by Harold et al (Nature Genetics) PICALM is stated to be involved in the transport of VAMP2, a protein that plays a role in "the fusion of synaptic vesicles to the presynaptic membrane in neurotransmitter release". If PICALM plays a direct role in the alteration of synapse structure then it can be viewed as an independent genetic factor in the development of AD, rather than a factor that contributes to A? levels. In addition to Corder et al's study which provides evidence for LOAD being caused by an overproduction of ? amyloid, the studies conducted by Harold et al and Lambert et al strongly suggest that LOAD can also be caused by a lack of clearance of ? amyloid from the brain (shown by the research evidence surrounding CLU, CR1 and PICALM). It may also be the case that genetic factors cause a structurally abnormal brain from birth, even if Alzheimer's symptoms do not present themselves until later on in lifexxii. It can be concluded from the vast amount of research surrounding Alzheimer's disease that it is a highly complex condition caused by multiple genetic variations. Although no perfect cure can be created for AD at present, recent developments in scientific knowledge and research methods might allow for more effective gene therapies to be developed in the near future. However, In the word's of Harold et al "additional and larger GWAS may be required to identify remaining susceptibility variants for Alzheimer's disease" and it is only once all of the susceptibility variants have been identified for Alzheimer's that an effective and lasting treatment can be synthesised.

References

ii http://alzheimers.org.uk/factsheet/401 iii Michael A van Es & Leonard H can den Berg, Alzheimer's disease beyond APOE, Nature Genetics, Volume 41, October 2009 iv http://en.wikipedia.org/wiki/Alzheimer%27s_disease v http://www.nhs.uk/conditions/dementia/Pages/Introduction.aspx vi Michael A van Es & Leonard H can den Berg, Alzheimer's disease beyond APOE, Nature Genetics, Volume 41, October 2009 vii Michael A van Es & Leonard H can den Berg, Alzheimer's disease beyond APOE, Nature Genetics, Volume 41, October 2009 viii http://www.ec-online.net/Knowledge/articles/genetics.html ix http://en.wikipedia.org/wiki/Apolipoprotein x Qiang Liu et al, Amyloid Precursor Protein Regulates Brain Apolipoprotein E and Cholesterol Metabolism through Lipoprotein Receptor LRP1, Neuron, Volume 56, Issue 1, 66-78, 4 October 2007 xi Michael A van Es & Leonard H can den Berg, Alzheimer's disease beyond APOE, Nature Genetics, Volume 41, October 2009 xii http://www.ec-online.net/Knowledge/articles/genetics.html xiii http://www.genome.gov/20019523 xiv Harold et al, Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease, Nature Genetics, Volume 41, Number 10, October 2009 xv Harold et al, Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease, Nature Genetics, Volume 41, Number 10, October 2009 xvi Lambert et al, Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease, Nature Genetics, Volume 41, Number 10, October 2009 xvii http://en.wikipedia.org/wiki/Clusterin xviii http://en.wikipedia.org/wiki/Complement_receptor_1 xix Lambert et al, Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease, Nature Genetics, Volume 41, Number 10, October 2009 xx http://www.genecards.org/cgi-bin/carddisp.pl?gene=PICALM xxi Harold et al, Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease, Nature Genetics, Volume 41, Number 10, October 2009 xxii Harold et al, Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease, Nature Genetics, Volume 41, Number 10, October 2009