New research at the Medical College of Georgia (MCG) has found tiny flaws on three chromosomes in patients with the most common type of Alzheimer’s disease. These flaws pave the way for discovery of the genes responsible for late-onset Alzheimer’s disease, in which symptoms begin after age 65. This new insight may lead to better ways to diagnose and treat the devastating illness.
Dr. Poduslo, a neuroscientist at MCG found the flaws studying DNA donated by Texas families affected by late-onset Alzheimer’s. She conducted the research 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.” Alzheimer’s disease 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,” Poduslo said.
In Texas Dr. Poduslo enrolled nearly 500 patients, including 15 large, extended families, in her state-funded DNA bank. 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 cases, can continue.
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 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, where APOE is a gene located on the lower half of the chromosome.
“We started looking at genes upstream and downstream of APOE,” she said, and as they examined the chromosome they found that the disease in some of the families was linked with markers downstream from APOE. This was evidence that Alzheimer’s disease, even the subcategory of late-onset, clearly can be subdivided into still more categories. This new information may also 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.
Poduslo also mathematically analyzed key factors such as the age of onset of first symptoms, gender and disease progression, up through the time of a final autopsy analysis of the resulting plaques and neuronal tangles in the brains of these patients.
“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.