Unique Genetic Profile for Lewy Body Dementia Uncovered

Lewy body dementia (LBD) is a disease associated with abnormal deposits of a protein called α-synuclein in the brain. These deposits, called Lewy bodies, affect neurons in the brain and lead to problems with thinking, movement, behavior, and mood. LBD is one of the most common causes of dementia, after Alzheimer’s disease and vascular disease.

Now, a team of investigators led by researchers at University of College London (UCL) has just released data from a comprehensive genome-wide association study showing that LBD has a unique genetic profile, distinct from those of Alzheimer’s disease or Parkinson’s disease.

Findings from the new study were published recently in The Lancet Neurology, in an article entitled “Investigating the Genetic Architecture of Dementia with Lewy Bodies: A Two-Stage Genome-Wide Association Study.”

“Dementia with Lewy bodies accounts for 10% to 15% of dementia cases, yet our understanding of it lags beyond the more well-known Alzheimer’s disease, partly because it’s commonly misdiagnosed,” explained senior study investigator Jose Bras, Ph.D., a UCL Institute of Neurology and Alzheimer’s Society senior research fellow. “Our findings clarify the disease’s distinctive genetic signature, which should, in the future, help improve clinical trials and lead to more targeted treatments.”

The research team genotyped 1743 patients with LBD – including both clinical samples and 1324 pathological samples assessed postmortem – and 4454 controls. Interestingly, two of the genetic loci that were found to be significantly associated with DLB-APOE and GBA—bore the same associations to DLB as they do to Alzheimer’s and Parkinson’s, respectively. Another one of the loci identified – SNCA – is also associated with Parkinson’s, but differently; the researchers found that a different part of the gene is linked to DLB. They also found preliminary evidence for a gene locus that had not been previously associated with DLB, but the results did not reach significance.

Remarkably, the investigators noticed that a few loci typically associated with Alzheimer’s and Parkinson’s do not appear to be associated with LBD. However, the researchers were able to identify a heritability estimate of LBD for the first time at 36%, which is similar to that of Parkinson’s. The heritability was particularly high for four specific chromosomes, suggesting that further research could focus on those chromosomes to identify novel loci.

“As the gene loci that had previously been associated with LBD were also implicated in Alzheimer’s and Parkinson’s, it was unclear if LBD’s genetic roots were simply a combination of the other two diseases,” noted lead study investigator Rita Guerreiro, Ph.D., a UCL Institute of Neurology and Alzheimer’s Society senior research fellow. “We’ve confirmed that instead it has its own unique genetic profile. The selection of study participants has been a substantial challenge in dementia trials. Our findings can be used to identify more clearly which type of dementia each person has, so that they can take part in the right clinical trial, which could lead to better treatments and diagnostic tools.”

The researchers also hope that by advancing the understanding of which genes play a role in LBD, their results will aid in the development of targeted therapies.

“LBD and Parkinson’s have many similarities, as people with LBD often develop Parkinson’s symptoms, and Parkinson’s often leads to dementia,” Dr. Bras remarked. “By understanding the genetic underpinnings, we can more effectively target treatments to the different groups.”

Doug Brown, Ph.D., director of research at Alzheimer’s Society, which funded the study, added that “dementia with Lewy bodies is often misunderstood as being a mixture of Alzheimer’s and Parkinson’s, but this confirms it’s actually a unique condition. Despite LBD being one of the most common forms of dementia in older people, until now there simply hasn’t been enough information on its causes, so the finding that up to 36% of cases might be genetically inherited is a real revelation.”

“As the largest and most detailed study of its kind, these results will be invaluable in future research, and it’s a great milestone on the road towards our goal of understanding and treating all forms of dementia,” Dr. Brown concluded.