Press release
Tuesday, February 16, 2021
The NIH-led study locates 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 may play a critical role in determining whether a person will suffer from Lewy body dementia, a devastating disorder that puzzles the brain with groups 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 links between the disease and Parkinson’s disease, but also suggested that people with Lewy body dementia may share genetic profiles similar to those with Parkinson’s disease. ‘Alzheimer’s.
“Lewy body dementia is a devastating brain disorder for which we do not have effective treatments. It often seems that patients suffer the worst from Alzheimer’s and Parkinson’s diseases. Our results support the idea that this may be because Lewy body dementia is caused by a spectrum of problems that can be observed in both disorders, ”said Sonja Scholz, MD, Ph.D., researcher of the NIH and Stroke’s National Institute of Neurological Disorders (NINDS) and lead author of the study. “We hope these results will act as a plan to understand the disease and develop new treatments.”
The study was led by the team of Dr. Scholz and researchers in the laboratory of Bryan J. Traynor, MD, Ph.D., senior researcher at the NIH’s National Institute on Aging (NIA).
Lewy body dementia usually affects people over 65 years of age. 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 often diagnosed with dementia with Lewy bodies, but are sometimes misdiagnosed with Alzheimer’s disease. Alternatively, many patients, who are initially diagnosed with Parkinson’s disease, may end up having difficulty thinking and mood caused by dementia in Lewy’s body. In both cases, as the disease worsens, patients become severely disabled and may die eight years after 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 gene (SNCA), the main protein found in Lewy bodies. Other studies have found that variants of the apolipoprotein E (APOE) gene, which are known to play a role in Alzheimer’s disease, may also have one in Lewy body dementia.
“Compared to other neurodegenerative disorders, very little is known about the genetic forces behind Lewy body dementia,” Dr. Traynor said. “To get a better understanding we wanted to study the genetic architecture of Lewy body dementia.”
To do so, they compared the chromosomal DNA sequences of 2,981 patients with Lewy body dementia with those of 4,931 healthy and aged control participants. Samples of participants of European descent were collected at 44 locations: 17 in Europe and 27 throughout 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 laboratories at the University of Health Sciences Uniformed Services and with the support of Henry M. Jackson. Foundation for the Advancement of Military Medicine.
Initially, they found that the five-gene sequences of patients with Lewy body dementia were often different from those of 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 be linked to Alzheimer’s and Parkinson’s diseases. The other three genes, SNCA, APOE, and GBA, had been implicated in previous studies and thus reinforced 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 patients with Lewy body dementia with a new set of 8,928 control subjects, confirming their initial results.
Additional analysis suggested that changes in the activity of these genes may cause 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 common and rare variants of 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,” Dr. Traynor said.
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 the patients in this study were more likely to suffer from Alzheimer’s or Parkinson’s than the age-controlled subjects. These predictions were maintained even after reducing the potential impact of genes known to 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, or Parkinson’s disease, on the other, did not overlap.
“While Alzheimer’s and Parkinson’s disease are very different molecular and clinically different disorders, our results support the idea that the problems that cause these diseases can also lead to 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 help with this effort, the team published the study’s genome sequence data in the Genotypes and Phenotypes Database (dbGaP), a National Library of Medicine website that researchers can freely search for new knowledge about the causes of Lewy body dementia and other disorders.
Article:
Chia, R., et al. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides information on 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 Treatments (NS003154) and the National Institute on Aging (AG000935).
NINDS (https://www.ninds.nih.gov) is the leading national funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use this knowledge to reduce the burden of neurological diseases.
Regarding the National Institute on Aging (NIA): NIA leads the U.S. federal government’s effort to conduct and support research on aging and the health and well-being of older people. Visit the NIA website for information on a number of aging topics in English and Spanish. Learn more about age-related cognitive change and neurodegenerative diseases through the Alzheimer’s-related Center for Dementia Education and Referral (ADEAR) website. Stay connected with NIA.
Regarding the National Institutes of Health (NIH):
NIH, the country’s medical research agency, includes 27 institutes and centers and is a component of the U.S. Department of Health and Human Services. NIH is the leading federal agency that conducts and supports basic, clinical, and translational medical research and investigates 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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