A gene called TRPC4AP may cause Alzheimer's disease, a new study that analyzed the genetic profile of two large Georgia families with high rates of late-onset Alzheimer's disease has found.
Headed by Dr. Shirley E. Poduslo, neuroscientist in the Medical College of Georgia Schools of Medicine and Graduate Studies and the Charlie Norwood Veterans Affairs Medical Center in Augusta pointed out that genetic variations called single nucleotide polymorphisms, or SNPs, are common in DNA, but this particular pattern of SNPs was seen in nine out of 10 affected family members.
On the other hand, the 10th family member had half the distinctive pattern. The SNPs were also found in the DNA of 36 percent of 200 other late-onset patients stored in the Alzheimers' DNA Bank.
"We were shocked; we had never seen anything like this before. If we looked at unaffected spouses, their SNPs were all different. The variants consistently found in affected siblings are suggesting there is something in this gene. Now we have to go back and find what is in this gene that is making it so unique for Alzheimer's patients," said Poduslo.
She said the variation was seen in the TRPC4AP gene, part of a large family of genes that is not well-studied but is believed to regulate calcium. Calcium is needed throughout the body but its dysregulation can result in inflammation, nerve cell death and possibly plaque formation as well
Poduslo also indicated that the finding provides new directions for research and possibly new treatment targets. It also shows the important role large families affected by a disease can have in determining the cause of the disease.
However, Poduslo said that it is needed to identify the specific genetic mutation, which will require sequencing the very large gene, or determining the order of the base pairs that form the rungs of the ladder-like DNA. An SNP represents a change in either side of a rung.
"The mutation could be a deletion of some of the nucleotides, could be an insertion, or something in the promoter gene that turns the gene off so it's never transcribed. It could be a wide variety of things, and that is what our next step is to identify the mutation," she said.
She also indicate that one of the families that provided the sentinel genetic information had 15 members, including five with Alzheimer's that started in their 60s and 70s; the second family had 14 members, six of whom had the disease. The disease incidence itself was notable and the incidence of the pattern of SNPs was equally so.
"This to me is very, very striking. Genetics and lifestyle either could be the biggest risk factors. We looked at these families very, very carefully to see what in their background may make them different and we couldn't come up with anything. They were farmers living fairly healthy lifestyles," said Poduslo.
The findings are published online in the American Journal of Medical Genetics.