Alzheimer's Disease

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Researchers believe several genes interact to cause most cases of Alzheimer's disease, but only one genetic risk factor, a variant of the ApoE gene, has been confirmed.

To find other genetic risk factors, which may speed development of prevention strategies, the National Institute on Aging (NIA) has started a more aggressive and cooperative approach led by Dr. Richard Mayeux, the Gertrude H. Sergievsky Professor of Neurology, Psychiatry, and Epidemiology and director of the Gertrude H. Sergievsky Center.

In the NIA's new Alzheimer's Disease Genetic Initiative, 10 Alzheimer's Disease Research Centers around the country are working rapidly to recruit a total of 1,000 families into a central resource accessible to all qualified Alzheimer's researchers.

The initiative began last summer after an NIA meeting with members of its centers. During the meeting, the participants noted that research results from different labs were not truly independent findings because most researchers were studying the same limited set of families. In July, the NIA gave the 10 centers, including Columbia's, extra money to recruit 1,000 families in the next three years.

The idea behind the new effort, Dr. Mayeux says, is to map out the rest of the genes that are involved in late-onset Alzheimer's and to foster the development of new therapies.

So far, only one genetic factor, the epsilon 4 variant of the apolipoprotein E gene, ApoE4, has been linked conclusively to the late-onset form of the disease, which is the most common.

An understanding of ApoE4 and the three genes that are linked to the early onset form of the disease has led most researchers to conclude that amyloid deposits found in the brains of patients are the primary cause of Alzheimer's. All four genes are involved either in the deposition or the processing of the amyloid polypeptide.

But many steps in the pathogenesis of the disease remain unknown, Dr. Mayeux says, including how amyloid deposits lead to the death of neurons. "We may understand the steps in the disease more fully with the discovery of more genes," he says.

"And we may discover genes that are involved in other pathways we don't know about yet. The vaccines and treatments under development are targeting the reduction of amyloid, but it's possible that strategy won't work if other earlier processes are more important."

Collecting DNA and medical data from 1,000 families in three years will be difficult, but not unreasonable, Dr. Mayeux says. Numerous families are needed to unravel the genetics of Alzheimer's because of the age when the disease strikes. Most people with the disease no longer have living parents from which to get samples and their children are too young to show any signs of the disease. So these studies have to rely on siblings; but identifying genes with sibling data means more families are required.

Studies attempting to locate genes associated with a disease like Alzheimer's rely on using genetic markers. Markers are well-characterized segments of DNA with a known location in the genome whose inheritance can be followed. If a marker is found frequently in those who have the disease as compared to those who don't, then this marker may be linked (or close to) the disease gene. Because of the late onset of Alzheimer's disease, it is often not possible to follow markers linked with a disease gene being passed down through the generations, which is why siblings are often studied. When studying siblings diagnosed with Alzheimer's disease, investigators analyze their DNA using hundred of markers in search of regions of the genome that are shared by the two siblings more often than expected. When these regions are found, it is possible that a disease gene is located close to the marker.

Families are considered for inclusion in the database if they have at least two affected members, preferably siblings, their disease began after age 60, and there are one or two other family members willing to participate. Immortalized cell lines and medical data from all recruited families are stored at the National Cell Repository for Alzheimer's Disease at Indiana University. Researchers can request DNA from the cell lines to perform genetic analyses and DNA sequencing. Jennifer Williamson, a Sergievsky Center genetic counselor in charge of recruiting from the New York metropolitan area, has already collected about 10 families.

Dr. Mayeux and project coordinator Susan LaRusse, staff associate in the Taub Center, also are distributing an operations manual to all centers that instructs each how to keep families anonymous and defines more precisely the characteristics of Alzheimer's disease stages to make sure all the researchers involved in the initiative identify the disease in the same way. The refinement of the stages should eventually help researchers correlate variations in the presentation of the disease with different genes.

Once more genetic factors in Alzheimer's are identified, researchers may be able to devise ways to prevent the disease. "Once Alzheimer's starts, I think there's probably no way to stop it," Dr. Mayeux says. "The only way we're going to do anything is to prevent it. And the only way to prevent it is to know who's genetically at risk."