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

Shiner, Tamara; Mirelman, Anat; Rosenblum, Yevgenia; Kavé, Gitit; Weisz, Mali Gana; Bar‐Shira, Anat; Goldstein, Orly; Thaler, Avner; Gurevich, Tanya; Orr‐Urtreger, Avi; Giladi, Nir; Bregman, Noa

doi:10.3233/jad-201295

Cited by 14 publications

(11 citation statements)

References 47 publications

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“…A similar trend was previously observed in a study of 298 patients with PD, where 3 of 6 carriers of both APOE‐ε4 and GBA severe mutations progressed to dementia (HR 2.95; 95% CI 0.80 to 10.90) 7 . A faster decline in MMSE in GBA carriers with the APOE ‐ε4 allele was also recently shown in 100 Ashkenazi Jewish patients with DLB 43 . The increased risk of cognitive impairment observed in carriers of both APOE ‐ε4 and GBA mutations is possibly due to the combination of neurodegenerative mechanisms mediated by these genotypes.…”

Section: Discussionsupporting

confidence: 84%

GBA and APOE Impact Cognitive Decline in Parkinson's Disease: A 10‐Year Population‐Based Study

et al. 2022

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Background Common genetic variance in apolipoprotein E (APOE), β‐glucocerebrosidase (GBA), microtubule‐associated protein tau (MAPT), and α‐synuclein (SNCA) has been linked to cognitive decline in Parkinson's disease (PD), although studies have yielded mixed results. Objectives To evaluate the effect of genetic variants in APOE, GBA, MAPT, and SNCA on cognitive decline and risk of dementia in a pooled analysis of six longitudinal, non‐selective, population‐based cohorts of newly diagnosed PD patients. Methods 1002 PD patients, followed for up to 10 years (median 7.2 years), were genotyped for at least one of APOE‐ε4, GBA mutations, MAPT H1/H2, or SNCA rs356219. We evaluated the effect of genotype on the rate of cognitive decline (Mini‐Mental State Examanation, MMSE) using linear mixed models and the development of dementia (diagnosed using standardized criteria) using Cox regression; multiple comparisons were accounted for using Benjamini−Hochberg corrections. Results Carriers of APOE‐ε4 (n = 281, 29.7%) and GBA mutations (n = 100, 10.3%) had faster cognitive decline and were at higher risk of progression to dementia (APOE‐ε4, HR 3.57, P < 0.001; GBA mutations, HR 1.76, P = 0.001) than non‐carriers. The risk of cognitive decline and dementia (HR 5.19, P < 0.001) was further increased in carriers of both risk genotypes (n = 23). No significant effects were observed for MAPT or SNCA rs356219. Conclusions GBA and APOE genotyping could improve the prediction of cognitive decline in PD, which is important to inform the clinical trial selection and potentially to enable personalized treatment © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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Section: Discussionsupporting

confidence: 84%

GBA and APOE Impact Cognitive Decline in Parkinson's Disease: A 10‐Year Population‐Based Study

et al. 2022

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“…Thus, it is probable that GBA carriers are still able to elicit an appropriate functional configuration needed for stimulus processing and task performance, possibly through the remaining sub-networks. Potentially, with disease progression, this mechanism will no longer suffice and cognitive function will likely deteriorate, unmasking the difference reported in previous studies (Shiner et al, 2021) of more severe cognitive decline in GBA-DLB patients.…”

Section: Discussionmentioning

confidence: 92%

Event-Related Oscillations in Dementia with Lewy Bodies with a Mutation in the GBA Gene

Rosenblum¹,

Maidan²,

Goldstein³

et al. 2021

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Introduction. In dementia with Lewy bodies (DLB), mutations in the GBA gene are associated with a more severe cognitive phenotype. In basic science, event-related oscillations have traditionally been used to explore the neurophysiological underpinnings of various aspects of cognitive performance. Here, we aimed to compare event-related oscillations in DLB patients who are carriers and non-carriers of GBA mutations.Method. EEG was recorded during a visual oddball task in eight clinically diagnosed Ashkenazi Jewish DLB patients with the N370S mutation in the GBA gene (GBA-DLB) and eleven DLB non-carriers. The time-frequency power and inter-trial phase coherence were calculated from the Morlet wavelet convolution from the Fz electrode.Results. Task performance and cognitive assessments were comparable between groups. While the within-non-GBA-DLB group analysis revealed a significant increase relative to the baseline in the delta-band power (p=0.01, Cohen's d=1.0), the within-GBA-DLB-group analysis did not detect any event-related power change. In contrast, both subgroups showed an increase relative to the baseline in the delta and theta bands inter-trial phase coherence (all p<0.03, d>1.3). The between-group analysis revealed that event-related power - but not coherence - was lower in GBA-DLB compared to non-carriers in the delta band (p=0.04, d=-0.9).Conclusions. GBA-DLB patients showed decreased delta-band power compared to non-carriers despite the similar cognitive performance, whereas inter-trial phase coherence was comparable in both groups. These findings suggest that in carriers, preserved inter-trial phase coherence possibly compensates for the impaired power by eliciting the appropriate functional configuration needed for stimulus processing and task performance.

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“…Finally, the TODA test can also be useful for the early and differential diagnosis of dementia with Lewy bodies (DLB). Indeed, recent findings support the possible usefulness of hyposmia as a prodromal biomarker because it is present in some clinically normal GBA mutation carriers [ 45 ], is common in idiopathic REM sleep behavior disorder [ 46 , 47 ] and in older adults carrying the APOE ε4 allele, which is the most robust genetic risk allele for AD [ 49 ], DLB [ 50 ] and DLB spectrum [ 51 ] independently of AD pathology [ 52 ]. In addition, APOE-ε4 being linked to hippocampal atrophy and learning/memory phenotypes across the AD/DLB spectrum [ 53 ], it highlights once more the relationship between olfactory dysfunction and cognitive condition.…”

Section: Discussionmentioning

confidence: 99%

Olfactory identification disorders due to Alzheimer’s disease: A new test from France to Quebec

et al. 2022

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Olfactory identification disorder is regarded as an early marker of Alzheimer’s disease (AD) and of similar diagnostic significance of biological or cognitive markers. Premature damage of the entorhinal olfactory cortex, the hippocampus and the orbitofrontal cortex characterize AD and suggest a specific impairment of olfactory identification. The use of psychophysical olfactory identification tests in clinical diagnostic practice is therefore strongly recommended, but not required. As these widespread tests are rarely used, an innovative test, adapted to this target group has been developed. It has been used and validated in a routine care protocol at different Memory Centers in France and in Quebec, Canada. A total of 157 participants were recruited: including 63 Alzheimer’s patients and 94 healthy controls. The test was composed of 14 odorants diluted into 4 different concentrations. A computer interface generated randomization of 6 odors per participant and the automatic calculation of identification scores, of perceptual thresholds and of composite scores. All participants underwent a Mini Mental Scale Examination within the previous three months or on the same day of the olfactory test. The Alzheimer’s patients had a score between 20 and 30 and healthy controls participants had a score above 28 without any loss of points on recalled items. The results show that our olfactory identification test is able to significantly differentiate Alzheimer’s patients from healthy controls (p < 0.001), and to distinguish the French population tested from the Quebec population (p < 0.001). This study highlights an olfactory identification disorder as a target for early diagnosis of AD. Its cultural qualities make it a potential candidate for differentiated calibration between France and Quebec.

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

Cited by 14 publications

References 47 publications

GBA and APOE Impact Cognitive Decline in Parkinson's Disease: A 10‐Year Population‐Based Study

GBA and APOE Impact Cognitive Decline in Parkinson's Disease: A 10‐Year Population‐Based Study

Event-Related Oscillations in Dementia with Lewy Bodies with a Mutation in the GBA Gene

Olfactory identification disorders due to Alzheimer’s disease: A new test from France to Quebec

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