GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study

Rongve, Arvid; Witoelar, Aree; Ruiz, Agustín; Athanasiu, Lavinia; Abdelnour, Carla; Clarimón, Jordi; Heilmann‐Heimbach, Stefanie; Hernández, Isabel; Moreno‐Grau, Sonia; Rojas, Itziar de; Morenas‐Rodríguez, Estrella; Fladby, Tormod; Sando, Sigrid Botne; Bråthen, Geir; Blanc‬, ‪Frederic; Bousiges, Olivier; Lemstra, Afina W.; Steenoven, Inger van; Londos, Elisabet; Almdahl, Ina Selseth; Pålhaugen, Lene; Eriksen, Jon Alm; Djurovic, Srdjan; Stordal, Eystein; Saltvedt, Ingvild; Ulstein, Ingun; Bettella, Francesco; Desikan, Rahul S.; Idland, Ane‐Victoria; Toft, Mathias; Pihlstrøm, Lasse; Snædal, Jón; Tárraga, Lluís; Boada, Merçé; Lleó, Alberto; Stefánsson, Hreinn; Stefánsson, Kāri; Ramı́rez, Alfredo; Aarsland, Dag; Andreassen, Ole A.

doi:10.1038/s41598-019-43458-2

Cited by 57 publications

(62 citation statements)

References 31 publications

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“…Although we, and now several others, have reported increased cross-sectional risk for dementia in people with PD who inherited an APOE ε4 allele [14][15][16] , our results here showed only a trend to an increased rate of progression to dementia in this group. These results mirror those for AD, where APOE ε4 is a strong and extensively replicated genetic risk factor; however, the impact of APOE ε4 on clinical progression to MCI or AD dementia in multivariate analyses is not clear.…”

Section: Discussioncontrasting

confidence: 96%

Multivariate prediction of dementia in Parkinson’s disease

Phongpreecha

Cholerton

Mata

et al. 2020

npj Parkinsons Dis.

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Cognitive impairment in Parkinson's disease (PD) is pervasive with potentially devastating effects. Identification of those at risk for cognitive decline is vital to identify and implement appropriate interventions. Robust multivariate approaches, including fixedeffect, mixed-effect, and multitask learning models, were used to study associations between biological, clinical, and cognitive factors and for predicting cognitive status longitudinally in a well-characterized prevalent PD cohort (n = 827). Age, disease duration, sex, and GBA status were the primary biological factors associated with cognitive status and progression to dementia. Specific cognitive tests were better predictors of subsequent cognitive status for cognitively unimpaired and dementia groups. However, these models could not accurately predict future mild cognitive impairment (PD-MCI). Data collected from a large PD cohort thus revealed the primary biological and cognitive factors associated with dementia, and provide clinicians with data to aid in the identification of risk for dementia. Sex differences and their potential relationship to genetic status are also discussed.

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Section: Discussioncontrasting

confidence: 96%

Multivariate prediction of dementia in Parkinson’s disease

Phongpreecha

Cholerton

Mata

et al. 2020

npj Parkinsons Dis.

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“…Supporting this hypothesis, p.P522R in PLCG2 might also have a protective effect on DLB and FTD [78]. For all three diseases (i.e., AD, FTD, and DLB), a genetic overlap has been reported suggesting shared pathogenic pathways which may include pathways related to PLCG2 [16,24,36,64]. Furthermore, patients with DLB frequently show amyloid pathology [53] that contributes to fast disease progression and cognitive impairment [1] suggesting that microglial reaction to amyloid pathology could mediate the protective role of p.P522R on both AD and DLB.…”

Section: Discussionmentioning

confidence: 85%

PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment

Kleineidam¹,

Chouraki²,

Próchnicki³

et al. 2020

Acta Neuropathol

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A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau 181 , total tau, and Aβ 1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau 181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau 181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ 1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade Agustin Ruiz and Alfredo Ramirez have contributed equally to this work. The members of the Alzheimer's Disease Neuroimaging Initiative (ADNI) group are listed in Acknowledgements section. Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc. edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report.

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“…Most of the included studies have predominantly recruited Caucasian people, so their findings have limited generalisability. Furthermore, the second GWAS investigating DLB was published after the completion of this systematic review in May 2019 . The GWAS confirmed the genetic associations of DLB with APOE ‐ε4 and GBA , and it reported a suggestive association between DLB and ZFPM1 .…”

Section: Discussionmentioning

confidence: 84%

“…In comparison with the field of molecular genetics of AD or PD, pertinent research investigating genetics of LBD is still at an early stage. The field of LBD genetics has recently joined the GWAS era . None of the reported genetic associations warrant routine genetic testing in clinical settings at present, and the field is far from translating the knowledge of genetics to clinical diagnostic and therapeutic applications.…”

Section: Discussionmentioning

confidence: 99%

Systematic review of genetic association studies in people with Lewy body dementia

Sanghvi

Singh

Morrin

et al. 2020

Int J Geriat Psychiatry

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Objectives Lewy body dementia (LBD) causes more morbidity, disability, and earlier mortality than Alzheimer disease. Molecular mechanisms underlying neurodegeneration in LBD are poorly understood. We aimed to do a systematic review of all genetic association studies that investigated people with LBD for improving our understanding of LBD molecular genetics and for facilitating discovery of novel biomarkers and therapeutic targets for LBD. Methods We systematically reviewed five online databases (PROSPERO protocol: CRD42018087114) and completed the quality assessment using the quality of genetic association studies tool. Results Eight thousand five hundred twenty‐one articles were screened, and 75 articles were eligible to be included. Genetic associations of LBD with APOE, GBA, and SNCA variants have been replicated by two or more good quality studies. Our meta‐analyses confirmed that APOE‐ε4 is significantly associated with dementia with Lewy bodies (pooled odds ratio [POR] = 2.70; 95% CI, 2.37‐3.07; P < .001) and Parkinson's disease dementia (POR = 1.60; 95% CI, 1.21‐2.11; P = .001). Other reported genetic associations that need further replication include variants in A2M, BCHE‐K, BCL7C, CHRFAM7A, CNTN1, ESR1, GABRB3, MAPT, mitochondrial DNA (mtDNA) haplogroup H, NOS2A, PSEN1, SCARB2, TFAM, TREM2, and UCHL1. Conclusions The reported genetic associations and their potential interactions indicate the importance of α‐synuclein, amyloid, and tau pathology, autophagy lysosomal pathway, ubiquitin proteasome system, oxidative stress, and mitochondrial dysfunction in LBD. There is a need for larger genome‐wide association study (GWAS) for identifying more LBD‐associated genes. Future hypothesis‐driven studies should aim to replicate reported genetic associations of LBD and to explore their functional implications.

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GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study

Cited by 57 publications

References 31 publications

Multivariate prediction of dementia in Parkinson’s disease

Multivariate prediction of dementia in Parkinson’s disease

PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment

Systematic review of genetic association studies in people with Lewy body dementia

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