Objective: We aimed to explore the frequency and clinical impact of APOε4 polymorphisms in a cohort of Ashkenazi Jewish (AJ) patients with Dementia with Lewy Bodies (DLB) who have a high GBA mutation carrier frequency.

Background: DLB is on a clinico-pathological spectrum between Parkinson’s disease (PD) and Alzheimer’s disease (AD). Mutations in the GBA gene are frequent among DLB and PD patients whereas the APOε4 polymorphism is a significant risk factor for AD but not PD

Methods: 81 AJ patients with DLB, underwent genotyping for the 8 known AJ GBA mutations, APOε polymorphisms and the LRRK2 G2019S mutation.

Results: 29.62% (n=24) of DLB patients were carriers of mutations in the GBA gene. Epsilon4 allele frequency in all DLB patients was 16.66%. 2.46% (n=2) were carriers of the LRRK2 mutations and were removed from further analysis. A higher frequency of epsilon4 allele was found in patients with DLB who were not carriers of GBA mutations (18.42%) compared to those who were carriers of GBA mutations (12.5%). GBA mutation carriers were younger at symptom onset (66.62 yrs vs 71.38 yrs, p=0.028). After adjusting for age and disease duration, GBA mutation carriers had poorer cognition as assessed by the MOCA (16.10 vs 19.46, p=0.039) and the MMSE (24.40 vs 21.47, p=0.025). Contrary to our previous results, on this expanded cohort we found no significant difference between the severity of parkinsonian symptoms as assessed by motor UPDRS in GBA vs non-GBA mutation carriers (34.86 vs 29.70, p=0.23). We found however, that the presence of an APOε4 polymorphism was associated with significantly less severe parkinsonism (motor UPDRS APOε4 vs non APOε4: 26.33 vs 33.51, p=0.016). APOε4 polymorphisms had no effect of age of onset of disease or cognitive measures except for Digit Span in which carriers of APOε4 polymorphisms achieved better results (15.17 vs 11.97, p=0.001).

Conclusions: We find a high frequency of APOε4polymorphisms among patients with DLB, with the highest frequency rates found among the patients who are non-carriers of mutations in the GBA gene. Furthermore, we find differing effects of GBA mutations and APOε4 polymorphisms on the clinical features of disease with GBA mutations impacting the disease age of onset and cognitive measures whereas the presence of APOε4 polymorphisms was associated with less severe parkinsonism. Studies on larger groups of patients will need to ascertain whether APOε4 polymorphisms have a distinct effect on disease course in DLB.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-impact-of-apo%ce%b54-polymorphisms-and-mutations-in-the-gba-gene-on-the-clinical-features-of-dementia-with-lewy-bodies-among-ashkenazi-jews/