Press release
Tuesday, February 16, 2021
NIH study finds five genes that may play a critical role in dementia by Lewy bodies.
In a study conducted by researchers at the National Institutes of Health, scientists found that five genes may play a critical role in determining whether a person will suffer from dementia with Lewy bodies, a devastating disease that riddled the brain with clusters of abnormal protein deposits called Lewy bodies. Lewy bodies are also a hallmark of Parkinson’s disease. The results, published in Nature Genetics, not only supported the disease’s links to Parkinson’s disease, but also suggested that people suffering from dementia with Lewy bodies may share genetic profiles similar to those who have Alzheimer’s disease.
“Lewy body dementia is a devastating brain disease for which we have no effective treatments. Patients often seem to suffer the worst from Alzheimer’s and Parkinson’s disease. Our results support the idea that this may be because dementia with Lewy bodies is caused by a spectrum of problems that can be seen in both disorders, ”said Sonja Scholz, MD, Ph.D., a researcher at the National Institute of NIH and Stroke Neurological Diseases (NINDS) and the study’s senior author. “We hope that these results will serve as a model for understanding the disease and developing new treatments.”
The study was conducted by the team of Dr. Scholz and laboratory researchers from Bryan J. Traynor, MD, Ph.D., senior researcher at the National Institute on Aging (NIA) at NIH.
Lewy body dementia usually affects people over 65. The first signs of the disease include hallucinations, mood swings and problems with thinking, movement and sleep. Patients who initially have cognitive and behavioral problems are usually diagnosed as having dementia with Lewy bodies, but are sometimes misdiagnosed with Alzheimer’s disease. Alternatively, many patients, who are initially diagnosed with Parkinson’s disease, may eventually have reasoning and mood difficulties caused by Lewy body dementia. In both cases, as the disease worsens, patients become severely disabled and may die within eight years of diagnosis.
A growing body of evidence suggests that 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 alpha-synuclein (SNCA) gene, the main protein found in Lewy bodies. Other studies have found that variants in the apolipoprotein E (APOE) gene, which is known to play a role in Alzheimer’s disease, may also play a role in Lewy body dementia.
“Compared to other neurodegenerative diseases, very little is known about the genetic forces behind Lewy body dementia,” said Dr. Traynor. “To better understand, 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 control participants of the same age. The samples were collected from participants of European descent in 44 locations: 17 in Europe and 27 in North America. DNA sequencing was led by Clifton Dalgard, Ph.D., and researchers at The American Genome Center, a series of state-of-the-art labs at Uniformed Services University of the Health Sciences and supported by the Henry M. Jackson Foundation for the Advancement of Military Medicine.
Initially, they found that the sequences of five genes in Lewy body dementia patients were often different from those in controls, suggesting that these genes may be important. It was the first time that two of the genes, called BIN1 and TMEM175, were implicated in the disease. These genes may also be linked to Alzheimer’s and Parkinson’s disease. The other three genes, SNCA, APOE and GBA, have been implicated in previous studies and therefore reinforced the importance of genes in dementia by Lewy bodies.
The researchers also saw differences in the same five genes when they compared the DNA sequences of 970 other 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 can lead to dementia and that the GBA gene may have a particularly strong influence on the disease. The gene encodes the instructions for beta-glycosylceramidase, a protein that helps the cell’s recycling system break down sugary fats. The researchers found that both the common and rare variants in the GBA gene are linked to dementia by Lewy bodies.
“These results provide a list of five genes that we strongly suspect play a role in dementia by Lewy bodies,” said Dr. Traynor.
Finally, to examine the apparent links between Lewy body dementia and other neurodegenerative diseases, the researchers analyzed data from previous studies on Alzheimer’s and Parkinson’s disease. They found that the genetic profiles of patients in this study were more likely to suffer from Alzheimer’s or Parkinson’s disease than controls of the same age. These predictions remained even after reducing the potential impact of known genes that cause Alzheimer’s and Parkinson’s diseases, such as 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, do not overlap.
“Although Alzheimer’s disease and Parkinson’s disease are very different molecularly and clinically, our results support the idea that the problems that cause these diseases can also happen in Lewy body dementia,” said Dr. Scholz. “The challenge we face in treating these patients is to determine what specific problems are causing dementia. We hope that studies like this will help doctors find accurate treatments for each patient’s condition. ”
To assist in this effort, the team published the study’s genome sequence data on the Genotypes and Phenotypes database (dbGaP), a National Library of Medicine website where researchers can freely search for new insights into the causes of dementia by Lewy bodies and other disorders.
Article:
Chia, R., et al. Genome sequencing analysis identifies new loci associated with dementia by Lewy bodies and provides information about the complex genetic architecture. Nature Genetics, February 15, 2021 DOI: 10.1038 / s41588-021-00785-3
This study was supported in part by the NIH Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NS003154) and the National Institute on Aging (AG000935).
NINDS (https://www.ninds.nih.gov) is the main national funder of research on the brain and nervous system. NINDS ‘mission is to seek fundamental knowledge about the brain and nervous system and use that knowledge to reduce the burden of neurological diseases.
About the National Aging Institute (NIA): The NIA leads the United States federal government’s efforts to conduct and support research on aging, health and well-being of the elderly. Visit the NIA website for information on a variety of aging topics in English and Spanish. Learn more about age-related cognitive changes and neurodegenerative diseases through the website of the Education and Reference Center for Alzheimer’s and Dementia Dementias (ADEAR). Stay connected with NIA!
About the National Institutes of Health (NIH):
NIH, the country’s medical research agency, includes 27 institutes and centers and is a component of the United States Department of Health and Human Services. NIH is the leading federal agency that conducts and supports basic, clinical and translational medical research, and is investigating the causes, treatments and cures for common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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