NEUROLOGY

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Two Gene Variants Associated With Alzheimer’s Risk Identified

To date, only four genes have been definitively associated with Alzheimer’s disease (AD). Three mutated genes-amyloid precursor protein (APP) and the presenilins (PS1 and PS2)-have been shown to cause the rare, early-onset familial form of the disease, which mostly occurs in middle age. Only one gene variant, apolipoprotein e4 or APO-e4, has been confirmed as a significant risk factor gene for the common form of late-onset AD, which typically strikes after age 65. The goal of Genome-wide association (GWAS) studies is to look for genetic associations of diseases with the DNA of individuals within specific populations. To date, such studies have been done on relatively small numbers of samples and have not been able to identify genetic variations of smaller effect. In the largest GWAS reported to date involving AD (6 September 2009, online issue of Nature Genetics), two new possible genetic risk factors for late-onset AD, the most common form of the disease, have identified. Results showed that not only variations in the sequence of the CLU and PICALM genes were associated with increased risk, but that there were also 13 gene variants that merit further investigation. Involving more than 16,000 DNA samples, one feature of this research was its use of publicly shared DNA samples and databases, including several supported by the National Institute on Aging (NIA) and other components of the NIH. The study used brain and blood tissues made available and analyzed by dozens of laboratories in the United Kingdom, Ireland, Germany, Belgium, Greece and the US. The two-stage study first used samples from people with AD and a control group free of the disease to locate CLU on chromosome 8 and PICALM on chromosome 11, and then replicated the findings in a second stage of testing. CLU (ApoJ/clusterin located on chromosome 8) and PICALM (phosphatidylinositol-binding clathrin assembly protein located on chromosome 11) are both potentially involved in important pathways involved in AD. While more study is needed to determine the roles of the CLU and PICALM variants in AD pathology, the study noted that CLU levels are often elevated when brain tissue is injured or inflamed. Increased levels of CLU are found in the brains and cerebrospinal fluids of AD patients. Neurons have trouble functioning in neurodegenerative diseases because as the disease progresses, the connections between neurons, or synapses, often break down. Senile plaques and associated beta-amyloid are another hallmark of AD. It has been hypothesize that PICALM may play a role in synaptic health and that it may also affect the levels of beta-amyloid deposits in the brain.

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