Two Genetic Risk Factors for Alzheimer Disease Discovered
October 6, 2009
In a genome-wide association study on Alzheimer disease (AD), considered the largest ever, an international team of researchers have identified two novel gene variants that may possibly increase the risk of developing late-onset Alzheimer, the most common form of the condition. The findings of the study are reported in the online issue of the journal Nature Genetics.
Denise Harold, Research Associate, Psychological Medicine, Cardiff University, UK, and co-workers, carried out the study in two stages to identify AD-related gene variants in DNA samples of over 16,000 people.
• Stage I: involving 3,941 AD patients and 7,848 controls, the researchers replicated the established association of apolipoprotein E gene (APOE) with AD. They observed a genome-wide significant association of single nucleotide polymorphisms (SNPs) at CLU gene and the 5’ of the PICALM gene that were previously unidentified as risk factors of AD.
• Stage II: the association of the two newly discovered loci with AD was replicated in 2,023 AD patients and 2,340 controls.
CLU, also known as APOJ gene, is located on chromosome 8 and codes for clusterin, a protein that offers protection to the brain. Variation in the gene has been suggested to alter its protective activity, and thereby contribute to the development of AD. Although the role of CLU in influencing AD risk is not clear, increased clusterin levels have been documented in the brains of AD patients. Studies in animal models have reported that CLU could be involved in amyloid deposit formation in the brain. The other gene, PICALM is present on chromosome 11, and codes for phosphatidylinositol-binding clathrin assembly protein. Several geneticists hypothesize that PICALM could play a role in synaptic health and alter the amount of beta-amyloid deposits in the brain.
Recently, Lambert et al (Nature Genetics, 2009) conducted a genome-wide association study in 2,302 AD patients and 5,328 controls, to identify the risk loci for AD. Two loci, one in CLU and the other within CR1, showed replicated evidence of their association with the degenerative condition. The CR1 gene, present on chromosome 1, encodes the complement component (3b/4b) receptor 1. Earlier studies have shown that CR1 and CLU are involved in the clearance of beta amyloid peptide, a chief component of amyloid plaques, which are the pathological signatures of AD.
The 2009 statistical report by the Alzheimer’s Association showed that AD, the most common form of dementia, affects approximately 5.3 million people in the US; among whom 5.1 million are above 65 years.
To date, genetic variations of four genes have been reported to be definitively associated with AD. Amyloid precursor protein (APP), presenilins genes (PS1 and PS2) are associated with the early-onset familial form of AD; and APOE4, present on chromosome 19, is the only documented significant risk factor gene for the late-onset of the neurological disorder. The current discovery of the genetic risk factors could further advance the understanding of the pathological mechanism, and aid in developing treatment modalities for the late-onset Alzheimer disease.
References
1. Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet. 2009 Oct;41(10):1088-93.
2. New Alzheimer’s genes uncovered. Press Release. Cardiff University. Last accessed Sept 19, 2009.
3. Lambert JC, Heath S, Even G, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet. 2009 Oct;41(10):1094-9.
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