Alzheimer’s disease (AD) is a neurodegenerative disease characterized by distinctive beta-amyloid protein plaques and neurofibrillary tangles in the brain, associated with progressive dementia. In the UK, Alzheimer’s disease affects around 417,000 people (according to the Alzheimer’s Society website) and is the leading cause of dementia in the elderly. Late onset Alzheimer's disease or LOAD (with an age of onset of greater than 65) is the main form of this disease, accounting for more than 90% of all cases. The public health burden of LOAD or sporadic AD in developed nations is generally increasing as the population ages.

Although mutations in key genes have been associated with the very rare, familial forms of early onset AD, only one genetic variant (APOE4) has been reliably associated with susceptibility to the common form of disease, although recent research has suggested that a variant of the CALHM1gene may also confer increased risk of LOAD (see previous news). Now new research has identified a new putative susceptibility variant in a gene on the X-chromosome, PCDH11X [Carrasquillo MM et al. (2009) Nat Genet. Jan 11 (Epub ahead of print)].

Writing in the journal Nature Genetics, the US researchers report the findings from a genome-wide association (GWA) study of around 2400 individuals with LOAD and a similar number of controls, all from the US and of European descent. The PCDH11X gene is expressed primarily in the brain and has been suggested to encode a form of neural receptor, making it a plausible candidate for involvement in the pathology of LOAD. Significantly increased disease risk was observed in women homozygous (having two copies) for the gene variant; the association was marginal in women with only one copy of the variant, and not statistically significant in men with a copy. The effect of this variant therefore appears to be gender-specific, since men have only one X chromosome and hence a maximum of one copy of the genetic factor in question. This is the first genetic susceptibility factor for LOAD identified that affects women, but not men, although the greater disease prevalence in women is attributed primarily to their increased longevity following diagnosis.

Comment: Lead researcher Dr Steven Younkin said: "It is exciting to find a new gene for Alzheimer's, particularly the first that has a gender-specific effect, but we have a lot more work to do to resolve the complex genetics of the disease" (see BBC news). Of note, LOAD is a multifactorial disease, thought to arise due to a combination of multiple genetic and environmental factors; each genetic variant linked to the condition is likely to be associated with relatively small effects in terms of disease risk. However, every new factor linked to the disease provides an opportunity for improved understanding of the disease process and possible interventions to prevent or limit pathology, as well as contributing to the overall picture of genetic susceptibility. Whether the reported new association will be reproducible, particularly in different ethnic populations, remains to be determined.

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