The Genetics of Dementia with Lewy Bodies: Current Understanding and Future Directions

Abstract

Purpose of ReviewDementia with Lewy bodies (DLB) is a neurodegenerative disease that can be clinically and pathologically similar to Parkinson’s disease (PD) and Alzheimer’s disease (AD). Current understanding of DLB genetics is insufficient and has been limited by sample size and difficulty in diagnosis. The first genome-wide association study (GWAS) in DLB was performed in 2017; a time at which the post-GWAS era has been reached in many diseases.Recent FindingsDLB shares risk loci with AD, in the APOE E4 allele, and with PD, in variation at GBA and SNCA. Interestingly, the GWAS suggested that DLB may also have genetic risk factors that are distinct from those in AD and PD.SummaryAlthough off to a slow start, recent studies have reinvigorated the field of DLB genetics and these results enable us to start to have a more complete understanding of the genetic architecture of this disease.

Clinical and neuropathological differences between Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies – current issues and future directions

“…; Orme et al . ). In addition, gene‐based mutation analyses of DLB and PDD has identified three missense mutations in PSEN1 and PSEN2 (three in DLB and one in PDD) (Meeus et al .…”

“…In addition, genetic differences within the particular loci identified to be shared between PD and DLB may be responsible for the differential regional affectation by the synucleinopathic process in the case of DLB compared to PD. Six missense mutations have been identified in the SNCA gene in PD whilst to date only two have been associated with diffuse neuropathological Lewy body disease (Rosborough et al 2017;Orme et al 2018). In addition, gene-based mutation analyses of DLB and PDD has identified three missense mutations in PSEN1 and PSEN2 (three in DLB and one in PDD) (Meeus et al 2012).…”

Association of MAPT H1 subhaplotypes with neuropathology of lewy body disease

“…2,4 Both PD (with or without dementia) and DLB have a well-recognized genetic component. [5][6][7][8] The microtubule-associated protein tau (MAPT) H1 haplotype is one of the strongest genetic risk factors for PD, 6 and it has also been associated with PDD 9 and DLB. 8,10 The MAPT gene contains two major haplotypes; the H1 haplotype is common, occurring in approximately 80% of neurologically normal subjects, whereas H2 is the rarer and generally only occurs in individuals of European ancestry.…”

“…Both PD (with or without dementia) and DLB have a well‐recognized genetic component . The microtubule‐associated protein tau ( MAPT ) H1 haplotype is one of the strongest genetic risk factors for PD, and it has also been associated with PDD and DLB .…”

“…2,4 Both PD (with or without dementia) and DLB have a well-recognized genetic component. [5][6][7][8] The…”