Association between the LRP1B and APOE loci and the development of Parkinson's disease dementia.
Parkinson’s disease
dementia
genome-wide
survival
Journal
Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537
Informations de publication
Date de publication:
02 05 2023
02 05 2023
Historique:
received:
09
06
2022
revised:
04
10
2022
accepted:
16
10
2022
medline:
3
5
2023
pubmed:
10
11
2022
entrez:
9
11
2022
Statut:
ppublish
Résumé
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 3923 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 [hazard 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 [hazard 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 [hazard 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.
Identifiants
pubmed: 36348503
pii: 6812546
doi: 10.1093/brain/awac414
pmc: PMC10151192
doi:
Substances chimiques
Apolipoproteins E
0
Biomarkers
0
LRP1B protein, human
0
Receptors, LDL
0
Types de publication
Meta-Analysis
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1873-1887Subventions
Organisme : Medical Research Council
ID : MR/L010305/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N026004/1
Pays : United Kingdom
Organisme : Parkinson's UK
ID : J-0901
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0701075
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0901254
Pays : United Kingdom
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.
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