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New Genetic Loci Identified for Lewy Body Dementia

A recent study, published in Nature used Genome Wide Association Studies to identify new risk loci associated with Lewy Body Dementia, and confirmed that it genetically overlaps with both Parkinson’s Disease and Alzheimer’s Disease.

Lewy Body Dementia

The genetic basis of Lewy Body Dementia (LBD) is not well understood. It is a clinically heterogeneous neurodegenerative disease, characterised by a progressive cognitive decline, Parkinsonism and visual hallucinations.

Post-mortem analyses have revealed that the disorder is distinguished by widespread cortical and limbic depositions of mutated forms of alpha synuclein proteins. These form Lewy Bodies and Lewy Neurites and are also a hallmark of Parkinson’s disease (PD). The majority of LBD patients also exhibit similar pathology to those with Alzheimer’s disease (AD), thus it has been hypothesised that LBD lies on a disease continuum between PD and AD.

Despite affecting an estimated 1.4 million individuals in the US, there are currently no effective disease modifying treatments available to slow disease progression. However, the recent advances in genome sequencing technologies provide an unprecedented opportunity to identify and characterise disease-associated genetic variation.

Risk Loci for Lewy Body Dementia

The researchers performed whole genome sequencing (WGS) in large cohorts of LBD patients and neurologically healthy controls. Their aims were to study the genetic architecture of the disease and produce a genetic resource for the scientific community.

Genome wide association analyses identified 5 independent risk loci. These were also replicated in an independent case-control cohort. 3 of these loci, GBA, APOE and SNCA were known risk loci of LBD. However, BIN1 and TMEM175 were newly identified risk loci. Notably, both have been implicated in other age related neurological diseases.

The BIN1 gene encodes a protein involved in endosomal trafficking. The depletion of this gene leads to increased amyloid beta production and promotes the propagation of tau pathology. The pathogenic impacts of this gene in LBD appear to be the same as in AD. Thus, mitigation of BIN1-mediated endosomal dysfunction could have therapeutic implications in both neurodegenerative diseases.

On the other hand, TMEM175 is a known Parkinson’s disease risk locus. Deficiency of this gene impairs lysosomal function and leads to increased deposition of phosphorylated alpha-synuclein. The identification of this gene underscores the role of lysosomal dysfunction in the pathogenesis of Lewy body diseases.

The Impact of Rare Genetic Variants

However, these loci only explain a small proportion of the heritability of LBD. To explore whether rare genetic variants contribute to the genetic risk of LBD, the team also performed genome wide aggregation tests. This rare variant analysis identified GBA as being associated with LBD. GBA encodes a lysosomal enzyme and is a known pleomorphic risk gene for LBD and PD.

They also leveraged this WGS data to explore the etiological relationship between AD, PD and LBD. They found that individuals diagnosed with LBD had a higher genetic risk for developing both AD and PD. Overall, this data confirms that the genetic architecture of LBD is complex and overlaps with the risk profiles of AD and PD.

Pathogenic Pathways of Lewy Body Dementia

Pathway enrichment analysis of LBD found several pathways which may be involved in LBD. These are related to the regulation of amyloid-beta formation, regulation of endocytosis, tau protein binding and others. Notably, regulation of amyloid-beta formation and tau protein binding has previously been implicated in the pathogenesis of Alzheimer’s disease. Similarly, endocytosis is particularly important in the pathogenesis of Parkinson’s disease. These findings support the hypothesis of overlapping disease-associated pathways in these common, age-related neurodegenerative diseases.  

These analyses highlight the contributions of both common and rare variants to the complex genetic architecture of LBD. The study identified new loci relevant to the pathogenesis of LBD and confirmed that LBD genetically overlaps with AD and PD. Determining shared molecular and genetic relationships between complex neurodegenerative diseases paves the way for precision medicine and aids the prioritisation of targets for therapeutic development. 

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