Genetic Factors in Lewy Body Dementia

Lewy body dementia is a neurodegenerative syndrome characterised by progressive cognitive decline, parkinsonism and visual hallucinations. Genetic studies indicate heritability accounts for up to one third of risk, implicating both rare mutations and common risk alleles. Key susceptibility genes include SNCA, encoding α-synuclein that aggregates into hallmark Lewy bodies, and GBA, in which variants modulate lysosomal function and confer a two- to threefold increase in disease risk. The APOE ε4 allele, established in Alzheimer’s disease, also influences risk and disease progression in Lewy body dementia, while MAPT haplotypes and variants in the SNCB gene further diversify the genetic architecture. Genome-wide association studies have uncovered additional loci with modest effect sizes, and bioinformatic analyses suggest involvement of lipid metabolism, immune regulation and synaptic function. Polygenic risk scores demonstrate promise in stratifying patients and distinguishing Lewy body dementia from Alzheimer’s and Parkinson’s disease, reflecting both shared and unique genetic signatures. Advances in multi-omic approaches and trans-ethnic meta-analyses are refining our understanding of global and population-specific risk factors, with implications for early diagnosis, biomarker development and targeted therapeutics.

Research from Nature Portfolio

Large-scale genome-wide analysis of European cohorts has reaffirmed the role of lysosomal enzyme gene variants and lipid-related risk alleles in disease susceptibility. Investigators conducted a genome-wide association study in over 80 000 individuals, identifying significant associations at the GBA locus and confirming the impact of the APOE ε4 allele on disease onset and progression. A suggestive locus on chromosome 16 linked to psychosis in Alzheimer’s disease emerged, pointing to overlapping pathways of synaptic dysfunction. These findings underscore a complex relationship between Lewy body dementia genetics and other neurodegenerative disorders, while highlighting targets for functional follow-up.

Genetic Factors in Lewy Body Dementia publication trend

The graph below shows the total number of articles in genetic factors in lewy body dementia across all publications each year (not limited to Nature Index journals).

Technical terms

Genome-wide association study (GWAS): An analysis scanning common genetic variants across the genome to identify loci associated with disease risk.

Polygenic risk score: A quantitative measure summarising the combined effect of multiple genetic variants on an individual’s disease susceptibility.

Synucleinopathy: A class of neurodegenerative disorders characterised by abnormal aggregation of α-synuclein protein.

Trans-ethnic meta-analysis: A statistical method combining genetic association data from diverse ancestral populations to identify shared and population-specific risk loci.

References

1. The Genetics of Dementia with Lewy Bodies: Current Understanding and Future Directions. Current Neurology and Neuroscience Reports (2018).
2. GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study. Scientific Reports (2019).
3. A genome-wide association study identifies a novel East Asian–specific locus for dementia with Lewy bodies in Japanese subjects. Molecular Medicine (2025).
4. Dementia with Lewy Bodies: Genomics, Transcriptomics, and Its Future with Data Science. Cells (2024).
5. Pinpointing novel risk loci for Lewy body dementia and the shared genetic etiology with Alzheimer’s disease and Parkinson’s disease: a large-scale multi-trait association analysis. BMC Medicine (2022).
6. Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases. Neurobiology of Aging (2015).
7. Assessment of genetic risk for improved clinical-neuropathological correlations. Acta Neuropathologica Communications (2020).
8. Genetic Architecture and Molecular, Imaging and Prodromic Markers in Dementia with Lewy Bodies: State of the Art, Opportunities and Challenges. International Journal of Molecular Sciences (2021).