A large U.S.-based research collaboration has discovered five genes—BIN1, TMEM175, SNCA, APOE, and GBA—associated with increased risk for developing Lewy body dementia, the second most common form of the progressive disease after Alzheimer’s.
Lewy body dementia impacts 10% to 25% of all dementia cases. Patients with this condition tend to be male and over the age of 65 years. They have varying degrees and types of symptoms but these include cognitive decline, Parkinson’s symptoms and visual hallucinations.
There is quite a big crossover with Parkinson’s disease and indeed some researchers believe that both Parkinson’s disease and Lewy body dementia are two disorders on a spectrum of Lewy body disease. Both are characterized by widespread deposits of dysfunctional α-synuclein proteins in the neurons and brain.
“Lewy body dementia is a devastating brain disorder for which we have no effective treatments. Patients often appear to suffer the worst of both 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 seen in both disorders,” said Sonja Scholz, M.D., Ph.D., a researcher at the NIH’s National Institute of Neurological Disorders and Stroke, who led the study.
“We hope that these results will act as a blueprint for understanding the disease and developing new treatments.”
To investigate the genetics of Lewy body dementia in more detail. Scholz and colleagues from a number of different U.S. research institutions and universities carried out whole-genome sequencing on 2981 individuals with Lewy body dementia and compared these with genomic data collected from 4391 healthy controls with no neurological disorders.
Using a genome-wide association study (GWAS) approach, the researchers identified five genes that were often mutated in individuals with this form of dementia, a finding they replicated in an independent cohort with 970 Lewy body dementia patients and 8928 controls.
Three of these genes, SNCA, APOE, and GBA, have been linked to Lewy body dementia in the past. However, as reported by the researchers in the journal Nature Genetics, two of the genes, BIN1 and TMEM175, had not previously been linked with this kind of dementia. Although BIN1 has been linked with Alzheimer’s and TMEM175 with Parkinson’s disease in other studies.
The GWAS analysis only explained some of the heritability of Lewy body dementia, which is thought to be around 10-11% overall. The researchers carried out an additional analysis to assess the impact of rare mutations on heritability and found that rare mutations in the GBA gene contribute significantly to the risk for Lewy body dementia. This gene encodes a protein, beta-glucosylceramidase, that breaks down glycolipids that may accumulate in lysosomes as cellular garbage.
The team also did some comparisons between patients with Alzheimer’s, Parkinson’s and Lewy body dementia. They found those with Lewy body dementia had a higher risk of developing both Parkinson’s and Alzheimer’s disease even after controlling for possible confounding factors, confirming links between the three diseases.
“While neurodegenerative diseases such as Alzheimer’s and Parkinson’s Disease present as distinct cellularly and clinically, our study suggests genetic influences for these diseases overlap with Lewy body dementia. The complex intersection of these diseases allows us to focus and select potential preventative approaches for military service members and veterans with risk factors of neurotrauma, stress and depression. We are enthusiastic to share this genomic data and its findings to the research community,” concluded study co-author Clifton Dalgard, Ph.D., a researcher at the Uniformed Services University of the Health Sciences in Bethesda.
To help with further efforts to target this currently incurable degenerative disorder, the research team has published the sequence data from the study on the dbGaP Portal.
