<scp><i>GBA</i></scp> and <scp><i>APOE</i></scp> Impact Cognitive Decline in Parkinson's Disease: A 10‐Year Population‐Based Study

Szwedo, Aleksandra A.; Dalen, Ingvild; Pedersen, Kenn Freddy; Camacho, Marta; Bäckström, David; Forsgren, Lars; Tzoulis, Charalampos; Winder‐Rhodes, Sophie; Hudson, Gavin; Liu, Ganqiang; Scherzer, Clemens R.; Lawson, Rachael; Yarnall, Alison; Williams‐Gray, Caroline H.; Macleod, Angus; Counsell, Carl; Tysnes, Ole‐Bjørn; Alves, Guido; Maple‐Grødem, Jodi

doi:10.1002/mds.28932

Cited by 62 publications

(56 citation statements)

References 65 publications

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“…Two of the cohorts (TPD and OPDC) recruited individuals of similar age to incident cohorts of Northern European ancestry, namely the cohorts included in the Parkinson's Incidence Cohorts Collaboration. 95 However, the remaining cohorts have a mean younger age than the observed average in incident population-based cohorts, which suggests these cohorts might not be representative of the wider PD population. Given these are non-incident cohorts, it is not possible to know when individuals who met criteria for dementia at baseline developed PDD, and so these were excluded from further analysis.…”

Section: Discussionmentioning

confidence: 96%

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Association between theLRP1BandAPOEloci and the development of Parkinson’s disease dementia

Real

Martínez-Carrasco

Lawton

et al. 2022

Brain

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Parkinson’s disease is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of Parkinson’s disease, particularly in the later stages of the disease. However, the rate of cognitive decline varies among Parkinson’s disease patients, and the genetic basis for this heterogeneity is incompletely understood. To explore the genetic factors associated with rate of progression to Parkinson’s disease dementia, we performed a genome-wide survival meta-analysis of 3,923 clinically diagnosed Parkinson’s disease cases of European ancestry from four longitudinal cohorts. In total, 6.7% of individuals with Parkinson’s disease developed dementia during study follow-up, on average 4.4 ± 2.4 years from disease diagnosis. We have identified the APOE ε4 allele as a major risk factor for the conversion to Parkinson’s disease dementia [hazards ratio = 2.41 (1.94–3.00), P = 2.32 × 10−15], as well as a new locus within the ApoE and APP receptor LRP1B gene [hazards ratio = 3.23 (2.17–4.81), P = 7.07 × 10−09]. In a candidate gene analysis, GBA variants were also identified to be associated with higher risk of progression to dementia [hazards ratio = 2.02 (1.21–3.32), P = 0.007]. CSF biomarker analysis also implicated the amyloid pathway in Parkinson’s disease dementia, with significantly reduced levels of amyloid β42 (P = 0.0012) in Parkinson’s disease dementia compared to Parkinson’s disease without dementia. These results identify a new candidate gene associated with faster conversion to dementia in Parkinson's disease and suggest that amyloid-targeting therapy may have a role in preventing Parkinson’s disease dementia.

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Section: Discussionmentioning

confidence: 96%

“…It is nevertheless reassuring that our study has identified some of the same genetic factors associated with higher risk of progression to dementia as large, incident population-based cohorts with long follow-up times such as APOE ε4 and GBA mutations, despite the potential limitations of large non-incident longitudinal cohorts. 95 …”

Section: Discussionmentioning

confidence: 99%

Association between theLRP1BandAPOEloci and the development of Parkinson’s disease dementia

Real

Martínez-Carrasco

Lawton

et al. 2022

Brain

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“…Our study has limitations that offer opportunities for further research. First, the age at diagnosis of our cohort (ie, 64 years) was lower than that commonly reported for the international PD consortiums (eg, 71 years for the Parkinson's Incidence Cohorts Collaboration) 81 ; this may limit the generalization of our findings and prompt future studies to replicate our results in a more representative study sample. Second, the relatively small sample size did not allow to test the stability of the clustering results by dataset split and to evaluate the contribution of other explanatory variables (eg, mood disorders or sleep disorders) possibly influencing memory functioning.…”

Section: Discussionmentioning

confidence: 70%

Memory Phenotypes In Early, De Novo Parkinson's Disease Patients with Mild Cognitive Impairment

et al. 2023

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BackgroundMemory deficits in mild cognitive impairment related to Parkinson's disease (PD‐MCI) are quite heterogeneous, and there is no general agreement on their genesis.ObjectivesTo define memory phenotypes in de novo PD‐MCI and their associations with motor and non‐motor features and patients’ quality of life.MethodsFrom a sample of 183 early de novo patients with PD, cluster analysis was applied to neuropsychological measures of memory function of 82 patients with PD‐MCI (44.8%). The remaining patients free of cognitive impairment were considered as a comparison group (n = 101). Cognitive measures and structural magnetic resonance imaging‐based neural correlates of memory function were used to substantiate the results.ResultsA three‐cluster model produced the best solution. Cluster A (65.85%) included memory unimpaired patients; Cluster B (23.17%) included patients with mild episodic memory disorder related to a “prefrontal executive‐dependent phenotype”; Cluster C (10.97%) included patients with severe episodic memory disorder related to a “hybrid phenotype,” where hippocampal‐dependent deficits co‐occurred with prefrontal executive‐dependent memory dysfunctions. Cognitive and brain structural imaging correlates substantiated the findings. The three phenotypes did not differ in terms of motor and non‐motor features, but the attention/executive deficits progressively increased from Cluster A, through Cluster B, to Cluster C. This last cluster had worse quality of life compared to others.ConclusionsOur results demonstrated the memory heterogeneity of de novo PD‐MCI, suggesting existence of three distinct memory‐related phenotypes. Identification of such phenotypes can be fruitful in understanding the pathophysiological mechanisms underlying PD‐MCI and its subtypes and in guiding appropriate treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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“…25 In PD, carriers of the APOE-ε4 allele were found to have both quicker cognitive decline compared with noncarriers and an increased risk of progression to dementia. 26 Prior studies have found rs9877502 on the 3q28 locus between GEMC1 and OSTN to be associated with higher CSF tau levels and identified a risk variant (rs1316356) for AD that is in linkage disequilibrium with this SNP. 4,5 In addition, GEMC1 has been recently reported to be a key molecule in multiciliated cell differentiation.…”

Section: Discussionmentioning

confidence: 99%

Genome‐Wide Meta‐Analysis of Cerebrospinal Fluid Biomarkers in Alzheimer's Disease and Parkinson's Disease Cohorts

Blauwendraat

Antar

et al. 2023

Movement Disorders

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BackgroundAmyloid‐β, phosphorylated tau (p‐tau), and total tau (t‐tau) in cerebrospinal fluid are established biomarkers for Alzheimer's disease (AD). In other neurodegenerative diseases, such as Parkinson's disease (PD), these biomarkers have also been found to be altered, and the molecular mechanisms responsible for these alterations are still under investigation. Moreover, the interplay between these mechanisms and the diverse underlying disease states remains to be elucidated.ObjectiveTo investigate genetic contributions to the AD biomarkers and assess the commonality and heterogeneity of the associations per underlying disease status.MethodsWe conducted genome‐wide association studies (GWASs) for the AD biomarkers on subjects from the Parkinson's Progression Markers Initiative, the Fox Investigation for New Discovery of Biomarkers, and the Alzheimer's Disease Neuroimaging Initiative, and meta‐analyzed with the largest AD GWAS. We tested heterogeneity of associations of interest between different disease statuses (AD, PD, and control).ResultsWe observed three GWAS signals: the APOE locus for amyloid‐β, the 3q28 locus between GEMC1 and OSTN for p‐tau and t‐tau, and the 7p22 locus (top hit: rs60871478, an intronic variant for DNAAF5, also known as HEATR2) for p‐tau. The 7p22 locus is novel and colocalized with the brain DNAAF5 expression. Although no heterogeneity from underlying disease status was observed for the earlier GWAS signals, some disease risk loci suggested disease‐specific associations with these biomarkers.ConclusionsOur study identified a novel association at the intronic region of DNAAF5 associated with increased levels of p‐tau across all diseases. We also observed some disease‐specific genetic associations with these biomarkers. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.

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

Cited by 62 publications

References 65 publications

Association between theLRP1BandAPOEloci and the development of Parkinson’s disease dementia

Association between theLRP1BandAPOEloci and the development of Parkinson’s disease dementia

Memory Phenotypes In Early, De Novo Parkinson's Disease Patients with Mild Cognitive Impairment

Genome‐Wide Meta‐Analysis of Cerebrospinal Fluid Biomarkers in Alzheimer's Disease and Parkinson's Disease Cohorts

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