by Julie Cleveland and Rebecca Logsdon, Ph.D.

For more than a decade, the UW ADRC has been on the forefront of research on the genetics of Alzheimer's disease (AD). Beginning with studies of families with multiple affected members, UW researchers have been one of the major groups linking three different genes to early-onset AD. These genes, located on chromosomes 1, 14 and 21, have been found in families where AD occurs in individuals younger than age 65. Investigating these genes and how they work is very important to learning how the brain changes in AD. The characteristic features of AD- neurofibrillary tangles, amyloid plaques, and neuronal death-are all caused by molecular functions that may be triggered by abnormal genes.

In studying families with dementia, UW researchers Drs. Thomas Bird, Gerald Schellenberg, and Ellen Wijsman, research nurse Ellen Nemens, postdoctoral fellows Parvie Poorkay-Navas and Ian D'Souza, and neuropathologist David Nochlin noticed certain families didn't fit the classic characteristics of AD, either in terms of clinical symptoms or the neuropathology in their brains after they died and were autopsied. They began to search for clues about why these families were different and discovered they suffered not from AD, but from a different type of dementia called frontotemporal dementia (FTD). In addition, the UW team examined the genetic characteristics of these families and discovered an abnormality on chromosome 17, a location that had already been linked with FTD.

Frontotemporal dementia has only begun to receive attention in the past few years. FTD is different from Alzheimer's disease in three ways:

1. Clinically--early on, memory is relatively good, whereas with AD memory is the main problem from the beginning. With FTD, memory is usually spared early in the disease but people have serious behavioral problems. They can be withdrawn, aggressive, anti-social, or disinhibited.

2. On brain imaging (MRI or CAT scan)--rather than the diffuse atrophy (decrease in size) throughout the brain seen with AD, the atrophy in the brains of people with FTD is usually confined to the frontal or temporal lobes.

3. Pathologically--when looking under the microscope at the brain of someone with FTD, the changes are not the same as those with AD. Although there may be neurofibrillary tangles, which also occur in AD, there are no amyloid plaques.

In addition, FTD typically affects people at a younger age than AD. FTD affects people in their 40's, 50's, and 60's, whereas AD is rare before age 65.

Dr. Bird's team of researchers began searching to try to find the specific gene linked to FTD. In 1998, Parvie Poorkaj-Navas, working in Dr. Gerry Schellenberg's lab, found a mutation of the "tau" gene, located on chromosome 17. This was the first discovery of a gene mutation causing FTD. Subsequently, many other research groups have confirmed this finding and have found different mutations in the tau gene in other families with FTD.

Researchers around the world are now working very hard to answer additional questions that have arisen, such as: Do all people with FTD have mutations in the tau gene? How do these mutations cause the disease? What's the relationship of FTD to AD? Are there any treatments for it? How many cases of it are there? How can you tell for certain if somebody has FTD or not?

It is becoming clear that FTD is more common than was originally recognized. Researchers now estimate that it may represent 10% of all dementia, and an even larger proportion of early-onset dementia.

"However," comments Bird, "the number of those cases of FTD that have mutations in the tau gene seems to be quite small, so it doesn't explain all the cases of FTD. It only explains a small number of those cases in which it is hereditary, when you see it multiple members of the family."

The UW ADRC continues to be in the forefront of research on the genetics of neurodegenerative disorders. The researchers, staff and volunteers who work on this effort are shedding new light that will one day lead to better strategies for treating or even preventing AD and other dementias.

For more information on FTD and tau mutations contact Ellen Nemens at (206) 764-2112 or 1-(800) 745-4511.

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