The Effect of GBA Mutations and APOE Polymorphisms on Dementia with Lewy Bodies in Ashkenazi Jews

Background: Glucocerebrosidase (GBA) gene mutations and APOE polymorphisms are common in dementia with Lewy bodies (DLB), however their clinical impact is only partially elucidated. Objective: To explore the clinical impact of mutations in the GBA gene and APOE polymorphisms separately and in combination, in a cohort of Ashkenazi Jewish (AJ) patients with DLB. Methods: One hundred consecutively recruited AJ patients with clinically diagnosed DLB underwent genotyping for GBA mutations and APOE polymorphisms, and performed cognitive and motor clinical assessments. Results: Thirty-two (32%) patients with DLB were carriers of GBA mutations and 33 (33%) carried an APOE epsilon 4 allele. GBA mutation carriers had a younger age of onset (mean [SD] age, 67.2 years [8.9] versus 71.97 [5.91]; p = 0.03), poorer cognition as assessed by the Mini-Mental State Examination (21.41 [6.9] versus 23.97 [5.18]; p < 0.005), and more severe parkinsonism as assessed with the Unified Parkinson's Disease Rating Scale motor part III (34.41 [13.49] versus 28.38 [11.21]; p = 0.01) compared to non-carriers. There were statistically significant interactions between the two genetic factors, so that patients who carried both a mild GBA mutation and the APOE epsilon 4 allele (n = 9) had more severe cognitive (p = 0.048) and motor dysfunction (p = 0.037). Conclusion: We found a high frequency of both GBA mutations and the APOE epsilon 4 allele among AJ patients with DLB, both of which have distinct effects on the clinical disease phenotype, separately and in combination.

Automated summary

The study found high frequencies of GBA mutations and the APOE epsilon 4 allele among AJ patients with DLB, with distinct effects on the clinical disease phenotype separately and in combination. GBA mutation carriers had earlier onset age, poorer cognition, and more severe parkinsonism compared to non-carriers. There were significant interactions between the two genetic factors, with patients carrying both mutations showing more severe cognitive and motor dysfunction.