Study of Genetics in Lewy Body Dementia Sheds Light on Disease Mechanisms

This study is an important first step in understanding the genetic aspects of Dementia with Lewy Bodies and helps to clarify the contribution of genetics to the development of this disease and its relationship to other neurodegenerative diseases.

Dementia with Lewy bodies (DLB), the second most common form of dementia among elderly people after Alzheimer’s disease, is characterized by difficulty walking, fluctuations in alertness, excessive movement during sleep, visual hallucinations, and mood changes in addition to cognitive impairment.

Despite the prevalence of the disease and the impact of its associated symptoms, DLB remains under-researched. It tends to be overshadowed by its better-known cousins, Alzheimer’s and Parkinson’s diseases. In fact, DLB is often considered to be part of a spectrum of dementia that runs between Alzheimer’s and Parkinson’s diseases.

Adding to this narrative, genetic association studies have long supported the idea that there is genetic overlap between DLB, Parkinson’s disease, and Alzheimer’s disease. Yet, the limited sample sizes of these studies makes it impossible to draw decisive conclusions from them.

To better understand the genetic basis of DLB, a recent study – partly funded by the Canadian Consortium on Neurodegeneration in Aging (CCNA) – undertook a genome-wide association study (GWAS) to identify its genetic risk factors.

This work, published in the January 2018 issue of Lancet Neurology, represents “the most comprehensive and well powered genetic study in dementia with Lewy bodies so far.”

GWAS look at the genetic information of a large number of people in order to determine which individual genetic differences are related to people developing a given condition, such as DLB. These studies have made significant contributions to our understanding of dementia generally.

The results of this GWAS on DLB show that – instead of being a combination of the genetic underpinnings underlying Parkinson’s and Alzheimer’s diseases – DLB has its own unique genetic profile. In addition, it suggests the genetic heritability of DLB is 36% (a genetic heritability of 0% would mean that getting a disease or not would have no relation to one’s genetic makeup, whereas a genetic heritability of 100% would mean getting the disease depends entirely on one’s genetic makeup).  This full characterization of the genetic architecture of DLB represents a stepping stone towards an improved understanding of the causes of not only DLB, but perhaps also Parkinson’s disease and Alzheimer’s disease, not to mention an improved appreciation of their shared and unique differences.

“This study is an excellent example of the strength of collaborative “big data” research to which the CCNA can contribute.” Dr. Richard Camicioli, Professor Department of Medicine, Division of Neurology, University of Alberta; Team Leader, CCNA Lewy Body Dementia Research team

This knowledge will have implications for both diagnosis and treatment – which depend on the successful modification of specific proteins that are involved in the disease mechanism. As a complete picture of the spectrum of dementia – from Parkinson’s through to Alzheimer’s disease emerges – the present model researchers work with (i.e. that of discrete diagnostic categories of dementia) may shift towards a more holistic view of these neurodegenerative conditions.

We are grateful for CCNA’s support to enable Canadian researchers to be a part of an international consortium studying the genetics of DLB, because the complexity of the genetics responsible for DLB requires the investigation of a very large dataset made up of cases from around the world. Only together can we obtain sufficient analytical power to separate disease-related genetic mutations from innocent variants.

More than half of DLB heritability remains to be explained, so the next step will be to conduct whole genome sequencing of the collected samples.

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By: Ekaterina Rogaeva, Ph.D. & Peter St George-Hyslop, Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, ON, Canada; CCNA Team 1 investigators.

The views and opinions expressed in this guest blog are those of the authors (individual CCNA scientists) and do not necessarily reflect the views of the Canadian Consortium on Neurodegeneration in Aging and its partner organizations.