New gene identified for risk of Alzheimer's disease

30 June 2008

A second major common susceptibility allele has been discovered for increased risk of Alzheimer’s disease [Dreses-Werringloer U. et al. (2008) Cell 133: 1149-1161], through a combination of epidemiological studies, bioinformatics and molecular biology.
 
Although the aetiology of Alzheimer’s disease is complex, the presence of clumps of amyloid precursor protein (APP) – known as amyloid plaques – is common to all sufferers of the disease, and is believed to be related to neurodegeneration. Whilst a number of genetic causes of the rare familial early-onset form of the disease have been identified (including mutations in APP itself and the presenilin enzymes involved in processing it), the much more common late-onset Alzheimer's disease is caused by a complex interplay between numerous genetic and environmental factors (see Bird TD (2008) Genet Med. 10(4):231-239 for a review).
 
Currently, only one common genetic allele with a substantial effect on Alzheimer’s disease risk has been verified. The APOE gene, more commonly associated with cardiovascular disease risk, is thought to play a role in clearing amyloid protein from the brain, possibly through its interaction with cholesterol. The disease risk associated with this gene remains one of the largest known for a complex disease; the APOE e4 allele (present in 15% of the population) increases the risk of late-onset Alzheimer’s disease by threefold for a single copy and up to 12-fold when two copies are present (see previous news). Several other genes are currently under investigation and many more are expected to be uncovered through an extensive genome-wide association study of 14,000 samples currently underway in the UK (see previous news).
 
The new gene proposed in this study – calcium homeostasis modulator 1 (CALHM1) – is located on a region of chromosome 10 that has previously been linked with Alzheimer’s disease (see previous news). It encodes a calcium ion channel protein present on the cell surface of neurons and is believed to be involved in controlling the cellular concentration of calcium ions, which is critical for the regulation of APP processing. Combined case-control studies, with a total of 3404 participants, indicate that a common polymorphism located within in the coding region of the gene has an overall allele-specific odds ratio of 1.44, resulting in approximately double the risk of disease when two copies are present. Like the APOE e4 allele, the high risk allele of CALHM1 is also associated with an earlier age of onset of the disease.
 
Comment: According to the Alzheimer’s Society, most of the current 700,000 people in the UK with dementia have late-onset Alzheimer’s disease, and the disease is becoming an ever increasing burden upon the health system and society at large as the population ages. There is therefore an urgent need to elucidate the underlying mechanisms of the disease, and the novel multi-disciplinary methods used in this study may play a crucial role towards that end. Although there is currently no way to prevent or cure the disease, it is hoped that identifying genetic factors associated with Alzheimer’s disease will help to identify those at highest risk, and ultimately to design better preventative and therapeutic strategies. However, translation of this hard-earned scientific knowledge into tangible clinical benefits is likely to take years of further research and development.

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