Five genes have been identified which may play a critical role in determining whether a person will suffer from Lewy body dementia.
The findings of the study not only support the disease’s ties to Parkinson’s disease, but also suggest that people who have Lewy body dementia may share similar genetic profiles to those who have Alzheimer’s disease.
“Lewy body dementia is a devastating brain disorder for which we have no effective treatments,” says Sonja Scholz, investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study.
“Our results support the idea that this may be because Lewy body dementia is caused by a spectrum of problems that can be seen in both disorders.
“We hope that these results will act as a blueprint for understanding the disease and developing new treatments.”
A growing body of evidence suggests genetics may play a role in the disorder and that some cases may be inherited.
Scientists have found that some of these rare cases can be caused by mutations in the gene for alpha-synuclein (SNCA), the main protein found in Lewy bodies.
Further studies have found that variants in the gene for apolipoprotein E (APOE), which is known to play a role in Alzheimer’s disease, may also play one in Lewy body dementia.
“Compared to other neurodegenerative disorders, very little is known about the genetic forces behind Lewy body dementia,” says Dr Bryan Traynor, senior investigator at the NIH’s National Institute on Ageing (NIA).
“To get a better understanding we wanted to study the genetic architecture of Lewy body dementia.”
To do this, they compared the chromosomal DNA sequences of 2,981 Lewy body dementia patients with those of 4,931 healthy, age-matched control participants.
Samples were collected from participants of European ancestry at 44 sites: 17 in Europe and 27 across North America.
Initially, they found that the sequences of five genes from the Lewy body dementia patients were often different from those of the controls, suggesting that these genes may be important.
It was the first time that two of the genes, called BIN1 and TMEM175, had been implicated in the disease.
These genes may also have ties to Alzheimer’s and Parkinson’s diseases.
The other three genes, SNCA, APOE, and GBA, had been implicated in previous studies, and thus, strengthened the importance of the genes in Lewy body dementia.
The researchers also saw differences in the same five genes when they compared the DNA sequences of another 970 Lewy body dementia patients with a new set of 8,928 control subjects, confirming their initial results.
Further analysis suggested that changes in the activity of these genes may lead to dementia and that the GBA gene may have a particularly strong influence on the disease. The gene encodes instructions for beta-glucosylceramidase, a protein that helps a cell’s recycling system break down sugary fats.
The researchers found that both common and rare variants in the GBA gene are tied to Lewy body dementia.
“These results provide a list of five genes that we strongly suspect play a role in Lewy body dementia,” said Dr. Traynor.
Finally, to examine the apparent links between Lewy body dementia and other neurodegenerative diseases, the researchers further analysed data from previous studies on Alzheimer’s and Parkinson’s disease.
They found that the genetic profiles of the patients in this study had higher chances of suffering from either Alzheimer’s or Parkinson’s disease than the age-matched control subjects.
These predictions held even after they lowered the potential impact of known Alzheimer’s and Parkinson’s disease-causing genes, like APOE and SNCA. Interestingly, the patient’s genetic risk profiles for Alzheimer’s disease, on the one hand, or Parkinson’s disease, on the other, did not overlap.
“Although Alzheimer’s and Parkinson’s disease are molecularly and clinically very different disorders, our results support the idea that the problems that cause those diseases may also happen in Lewy body dementia,” adds Dr Scholz.
“The challenge we face in treating these patients is determining which specific problems are causing the dementia. We hope studies like this one will help doctors find precise treatments for each patient’s condition.”
