Scientists Identify Two Gene Variants Associated with Alzheimer's Risk

In the largest genome-wide association study (GWAS) reported to date involving Alzheimer's disease, scientists have identified two new possible genetic risk factors for late-onset Alzheimer's, the most common form of the disease. The study, which pooled DNA samples from a number of European and U.S. groups, not only associated variations in the sequence of the CLU and PICALM genes with increased risk, but also found another 13 gene variants that merit further investigation, according to findings presented in the September 6, 2009, online issue of Nature Genetics. 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 National Institutes of Health.

To date, only four genes have been definitively associated with Alzheimer's disease. 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 Alzheimer's, which typically strikes after age 65. GWAS studies look for genetic associations with a disease in the DNA on all of the chromosomes in a specific population of individuals. 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. But now, GWAS studies in very large sample sets are able to identify these elusive genetic variations.

"GWAS research is entering a new phase of discovery, with much larger sample sizes made available for analysis due to highly collaborative researchers and rapid DNA sample and data sharing," said Marcelle Morrison-Bogorad, Ph.D., director of the NIA Division of Neuroscience. "Identifying gene variants like CLU and PICALM advances our understanding of the many genetic factors that may contribute to overall risk for this devastating neurological disorder and how these genes affect the development of Alzheimer's. This knowledge may then lead to novel disease pathways that can be targeted to develop new treatments."

The collaborative consortium led by Julie Williams, Ph.D., and her colleagues at the School of Medicine at Cardiff University, Wales, used brain and blood tissues made available and analyzed by dozens of laboratories in the United Kingdom, Ireland, Germany, Belgium, Greece and the United States. The two-stage study first used samples from people with Alzheimer’s 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 Alzheimer’s pathology, the researchers 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 Alzheimer's 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 Alzheimer's disease. Geneticists 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.

The U.S. laboratories contributing samples to the study were: NIA's Laboratory of Neurogenetics, Bethesda, Md., and NIA-funded scientists at Washington University School of Medicine, St. Louis; Mayo Clinic College of Medicine, Jacksonville, Fla.; and Mayo Clinic and Mayo Foundation, Rochester, Minn. Samples were also provided by institutions supported by other NIH components, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Human Genome Research Institute, the National Institute of Neurological Disorders and Stroke and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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