News release
Tuesday, February 16, 2021
NIH-led study pinpoints five genes that may play a critical role in Lewy body dementia.
In a study led by researchers at the National Institutes of Health, scientists found that five genes could play a critical role in determining whether someone is suffering from Lewy body dementia, a devastating condition that the brain sees through with clumps of abnormal protein deposits, Lewy called bodies. Lewy bodies are also a hallmark of Parkinson’s disease. The results, published in Nature Genetics, not only supported the disease’s link to Parkinson’s disease, but also suggested that people with Lewy body dementia may share similar genetic profiles as people with Alzheimer’s.
“Lewy body dementia is a devastating brain disorder for which we have no effective treatments. Patients often seem to have the worst of Alzheimer’s and Parkinson’s. Our results support the idea that this may be because Lewy body dementia is caused by a spectrum of problems seen in both conditions, ”said Sonja Scholz, MD, Ph.D., researcher at NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and the study’s senior author. “We hope these results will serve as a blueprint for understanding the disease and developing new treatments.”
The study was led by Dr. Scholz and researchers in the lab of Bryan J. Traynor, MD, Ph.D., senior investigator at NIH’s National Institute on Aging (NIA).
Lewy body dementia usually affects people over the age of 65. Early signs of the disease include hallucinations, mood swings, and problems thinking, moving, and sleeping. In patients who initially have cognitive and behavioral problems, Lewy body dementia is usually diagnosed, but Alzheimer’s disease is sometimes incorrectly diagnosed. Alternatively, many patients initially diagnosed with Parkinson’s disease may eventually develop problems with thinking and mood caused by Lewy body dementia. In both cases, patients become severely disabled as the disease worsens and may die within eight years of diagnosis.
A growing body of evidence suggests that genetics may play a role in the condition and that some cases may be inherited. Scientists have found that some of these rare cases could be caused by mutations in the gene for alpha-synuclein (SNCA), the main protein found in Lewy bodies. Further studies have shown that variants in the apolipoprotein E (APOE) gene, which are 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 gain 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 descent at 44 sites: 17 in Europe and 27 in North America. The DNA sequencing was led by Clifton Dalgard, Ph.D., and researchers at The American Genome Center, a series of state-of-the-art laboratories at the Uniformed Services University of the Health Sciences and supported by the Henry M. Jackson Foundation to advance the military. medicine.
Initially, they found that the sequences of five genes from the Lewy body dementia patients often differed 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 involved in the disease. These genes may also have links to Alzheimer’s and Parkinson’s disease. The other three genes, SNCA, APOE and GBA, were involved in previous studies and thus enhanced 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 an additional 970 Lewy-body dementia patients with a new set of 8,928 controls, confirming their initial results.
Further analysis suggested that changes in the activity of these genes can lead to dementia and that the GBA gene can have a particularly strong influence on the disease. The gene codes 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 linked 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 investigate the apparent links between Lewy body dementia and other neurodegenerative diseases, the researchers further analyzed data from previous studies of Alzheimer’s and Parkinson’s disease. They found that the genetic profiles of the patients in this study were more likely to suffer from Alzheimer’s or Parkinson’s disease than the controls of the same age. These predictions persisted even after they lowered the potential impact of known genes that cause Alzheimer’s and Parkinson’s disease, such as APOE and SNCA. Interestingly, the patient’s genetic risk profiles for Alzheimer’s disease on the one hand and Parkinson’s disease on the other did not overlap.
“Although Alzheimer’s disease and Parkinson’s disease are molecularly and clinically very different disorders, our results support the idea that the problems these diseases cause may also occur in dementia with Lewy bodies,” said Dr. Scholz. “The challenge we face in treating these patients is to determine which specific problems are causing dementia. We hope that studies like these will help doctors find precise treatments for every patient’s condition. “
To help with this, the team published the study’s genome sequence data in the database of Genotypes and Phenotypes (dbGaP), a National Library of Medicine website where researchers can freely search for new insights into the causes of Lewy body dementia and other conditions. .
Item:
Chia, R., et al. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insight into the complex genetic architecture. Nature Genetics, Feb. 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 leading funder of brain and nervous system research. NINDS ‘mission is to seek fundamental knowledge about the brain and nervous system and use that knowledge to reduce the burden of neurological disorders.
About the National Institute on Aging (NIA): NIA leads the US federal government’s efforts to conduct and support research on aging and the health and wellbeing of the elderly. Visit the NIA website for information on a range of aging topics in English and Spanish. Learn about age-related cognitive change and neurodegenerative diseases through the Alzheimer’s and Related Dementias Education and Referral Center (ADEAR) Center website. Stay connected with NIA!
About the National Institutes of Health (NIH):
NIH, the national medical research agency, includes 27 institutes and centers and is part of the United States Department of Health and Human Services. NIH is the premier federal agency that conducts and supports basic, clinical, and translational medical research, exploring the causes, treatments, and cures for both common and rare diseases. To learn more about NIH and its programs, visit www.nih.gov.
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