Tiny flaws have been found on three chromosomes in patients with the most common type of Alzheimer's disease by a researcher at the Medical College of Georgia.
These flaws pave the way for discovery of the genes responsible for late-onset Alzheimer's, in which symptoms begin after age 65, and lead to better ways to diagnose and treat the devastating disease, said Dr. Shirley E. Poduslo, neuroscientist.
Dr. Poduslo found the flaws studying DNA donated by Texas families affected by late-onset Alzheimer's while she was director of basic research for the Department of Neurology at Texas Tech University Health Sciences Center in Lubbock. Her research is published in the December issue of the British journal NeuroReport.
Now Dr. Poduslo, who joined the MCG faculty in November, has established a similar DNA bank for patients and their families from throughout Georgia and South Carolina to enable future studies.
"If you live to be 65, you have a 5 percent chance of developing Alzheimer's disease," Dr. Poduslo said. "If you live to be 85, you have a 50 percent chance. If you have a family history, there is an increased risk, no doubt about it," she said of the disease that affects about 4 million Americans today with a health care tab of $80 billion. "As our baby boomers age and retire, we are going to have a national crisis on our hands."
In Texas she enrolled nearly 500 patients, including 15 large, extended families, in her state-funded DNA bank. She was overwhelmed by the response of Texans. "It's something the families can do and it's something that is not difficult for them to do," Dr. Poduslo said of the process of collecting family histories, patients' medical records and blood. She's hoping for a similar response from Georgians and South Carolinians so that work to uncover the genetics of late-onset disease - which accounts for about 95 percent of Alzheimer's - can continue.
"We have really good evidence now that even late-onset is genetic," she said. Years ago, researchers identified a gene, APOE 4, as a risk factor for Alzheimer's, and subsequently several genetic mutations were identified as causes for the more rare, but more aggressive early-onset Alzheimer's.
Armed with DNA from15 extended families with late-onset disease, Dr. Poduslo began looking at chromosome 19; APOE is a gene on the lower half of that chromosome. "We started looking at genes upstream and downstream of APOE," and as they looked, they found that the disease in some of the families was linked with markers downstream from APOE. This is evidence that Alzheimer's disease - even the subcategory of late-onset - clearly can be subdivided into still more categories, information, again, that may be critical to improved diagnosis and treatment.
"I assumed naively that all families would be linked with a mutation in one gene because Alzheimer's was one disease," she said. "That is not what we are finding. What we have found out is that we have three families with the disease linked with markers on chromosome 12. We have four families linked with markers on chromosome 19 and we have one family linked with markers on chromosome 3. What that means is, yes, Alzheimer's definitely is genetic in these families and there are probably multiple causes for this disease," she said, noting that there is no known relationship between chromosomes 19, 12 and 3.
She also mathematically analyzed key factors such as the age of onset of first symptoms, gender and disease progression up through final autopsy analysis of the resulting plaques and neuronal tangles in the brains of these patients.
"Age of onset is becoming very important in our studies; when did the symptoms first start?" she said. What the first symptoms are and the stages of the disease - trouble with words, uncontrollable outbursts or slowness of movement - also seem to better define the disease.
"We now have to go back and identify the mutated genes," she said. "Once we identify the mutated genes, we are going to be able to start to correlate all of this. For example, chromosome 19 may affect people more when they are over age 75 and they may have more problems with outbursts of anger and may have an increased number of plaques in certain areas of the brain. What I am thinking is that we are going to be able to start subdividing this disease into specific groups."
That subdivision will help physicians optimize treatment, something that is becoming increasingly important with the large number of new therapies under study, she said. With the identification of responsible genes, these protocols might one day include gene therapy to cure the disease.
Dr. Poduslo hopes to retrieve the DNA material she collected in Texas as she builds a new bank of material from patients and families in Georgia and South Carolina.
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