Objective: To perform a comprehensive analysis of genes previously implicated in dementia with Lewy bodies (DLB) by exome sequencing of a pathologically confirmed DLB cohort.

Background: DLB is the second most common dementia after Alzheimer disease. The pathogenesis of DLB is largely unknown, but an increasing number of genetic factors have been implicated. Despite these insights, the frequency at which pathogenic mutations occur in DLB patients is unknown and we therefore undertook a comprehensive genetic analysis.

Methods: We performed exome sequencing in 111 pathologically confirmed DLB patients from the Johns Hopkins Brain Resource Center and assessed eight genes previously implicated in DLB for pathogenic missense mutations.

Results: Exome sequencing identified pathogenic mutations in GBA, APP, PSEN1 and in LRRK2. In total, 27 cases were detected who carried at least one pathogenic mutation. The most common mutations were found in GBA (13% of the entire cohort). Surprisingly, heterozygous PSEN1 mutations were present in 10% of cases and 2% were found to carry a pathogenic APP mutation. In addition, we identified a novel LRRK2 mutation (p.P815T) that is possibly pathogenic. In support of prior evidence, the APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value < 0.001). No pathogenic mutations were found in SNCA, MAPT or in PSEN2 suggesting that mutations in these genes are not frequent causes of DLB.

Conclusions: This comprehensive genetic analysis in pathologically confirmed DLB cases demonstrated that nearly 25% of DLB cases carry pathogenic mutations. This finding highlights the crucial role that molecular genetic defects play in the pathogenesis of this common neurodegenerative disorder and strongly support the notion that DLB occurs along a continuum between Parkinson’s disease and Alzheimer dementia.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/exome-sequencing-in-dementia-with-lewy-bodies/