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NIH Research Matters

July 21, 2006

New Genetic Clues to Dementia

This week, two research groups report they have uncovered genetic mutations that underlie two different forms of dementia. One group discovered genetic mutations that cause a large proportion of inherited familial frontotemporal dementia (FTD), a rare brain disorder that usually affects people between 40 and 64 with symptoms including personality changes and inappropriate social behavior. Another group identified alterations in a gene that may contribute to dementia with Lewy bodies (DLB), the second most common form of dementia among the elderly after Alzheimer's disease.

a Lewy body

The light purple sphere near the center of the image is a Lewy body. Image courtesy of Kondi Wong, Armed Forces Institute of Pathology.

Geneticist Dr. Michael Hutton of the Mayo Clinic College of Medicine in Jacksonville, Florida, led an international scientific team funded in part by NIH's National Institute on Aging (NIA) to discover the new gene for FTD. In the July 16, 2006 online edition of Nature, they describe the role of the progranulin, or PGRN, gene, which makes a growth factor protein that stimulates cell division and motility during embryonic development, wound repair and inflammation

The scientists say it's unclear what role progranulin plays in the normal brain, but in the FTD families, the PGRN mutations appear to cut short the assembly process for the protein in brain nerve cells (neurons), and the lack of progranulin eventually causes neurons to die. Understanding how this mutation helps bring about neuronal death might help scientists better understand the different pathways that cause dementia.

"This new finding is an important advance in our understanding of frontotemporal dementia," says NIA director Richard J. Hodes.

In the other study, reported in the journal Neurology, researchers found that alterations in the gene that codes for an enzyme called glucocerebrosidase (GBA) may contribute to the development of DLB. Mutations in this gene had previously been identified as the cause of Gaucher disease, a rare, inherited metabolic disorder.

DLB is named for Lewy bodies, the abnormal clumps of protein that develop inside nerve cells in both DLB and Parkinson's disease. People affected by DLB often show symptoms of Alzheimer's and Parkinson's disease, but most experts now consider DLB to be a distinct disorder. At least 5% of people age 85 and older are thought to have DLB, and the condition accounts for about one-fifth of all cases of dementia. There currently is no good treatment.

A research group led by Dr. Ellen Sidransky of NIH's National Human Genome Research Institute sequenced DNA from autopsy samples that had been carefully examined and classified by neuropathologists at the University of Pennsylvania. Dr. Sidransky's group found mutations in the GBA gene in eight of the 35 patients with DLB. That rate (23%) is nearly 40 times higher than the frequency of GBA mutations in the general population. In contrast, only one of 28 patients with "classic" Parkinson's disease had a GBA alteration, while no mutations were found among 12 patients with multiple system atrophy, another condition that can bring dementia.

"Our findings are particularly significant because this is among the first examples of a genetic change associated with dementia with Lewy bodies," Dr. Sidransky said.

These results offer intriguing new avenues for exploring the basic mechanisms at the cellular level that lead to dementia.

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Editor: Harrison Wein, Ph.D.
Assistant Editors: Vicki Contie, Carol Torgan, Ph.D.

NIH Research Matters is a weekly update of NIH research highlights from the Office of Communications and Public Liaison, Office of the Director, National Institutes of Health.

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This page last reviewed on December 3, 2012

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