Association of glucocerebrosidase polymorphisms and mutations with dementia in incident Parkinson's disease

Kristin Aaser Lunde; Janete Chung; Ingvild Dalen; Kenn Freddy Pedersen; Jan Linder; Magdalena E Domellöf; Eva Elgh; Angus D Macleod; Charalampos Tzoulis; Jan Petter Larsen; Ole-Bjørn Tysnes; Lars Forsgren; Carl E Counsell; Guido Alves; Jodi Maple-Grødem

doi:10.1016/j.jalz.2018.04.006

Association of glucocerebrosidase polymorphisms and mutations with dementia in incident Parkinson's disease

Alzheimers Dement. 2018 Oct;14(10):1293-1301. doi: 10.1016/j.jalz.2018.04.006. Epub 2018 May 21.

Authors

Affiliations

¹ The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway; Centre for Organelle Research, University of Stavanger, Stavanger, Norway.
² The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.
³ The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway; Department of Neurology, Stavanger University Hospital, Stavanger, Norway.
⁴ Department of Pharmacology and Clinical Neuroscience, Neurology, Umeå University, Umeå, Sweden.
⁵ Department of Pharmacology and Clinical Neuroscience, Neurology, Umeå University, Umeå, Sweden; Department of Psychology, Umeå University, Umeå, Sweden.
⁶ Department of Psychology, Umeå University, Umeå, Sweden.
⁷ Institute of Applied Health Sciences, Polwarth Building, University of Aberdeen, Aberdeen, UK.
⁸ Department of Neurology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
⁹ Network for Medical Sciences, University of Stavanger, Bergen, Norway.
¹⁰ The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway; Department of Neurology, Stavanger University Hospital, Stavanger, Norway; Department of Mathematics and Natural Sciences, University of Stavanger, Stavanger, Norway.
¹¹ The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway; Centre for Organelle Research, University of Stavanger, Stavanger, Norway. Electronic address: [email protected].

PMID: 29792872
DOI: 10.1016/j.jalz.2018.04.006

Abstract

Introduction: Both polymorphisms and mutations in glucocerebrosidase (GBA) may influence the development of dementia in patients with Parkinson's disease.

Methods: Four hundred forty-two patients and 419 controls were followed for 7 years. Dementia was diagnosed using established criteria. Participants were analyzed for GBA genetic variants, including E326K, T369M, and L444P. Associations between GBA carrier status and dementia were assessed with Cox survival analysis.

Results: A total of 12.0% of patients with Parkinson's disease carried a GBA variant, and nearly half (22/53) of them progressed to dementia during follow-up. Carriers of deleterious GBA mutations (adjusted hazard ratio 3.81, 95% confidence interval 1.35 to 10.72; P = .011) or polymorphisms (adjusted hazard ratio 1.79; 95% confidence interval 1.07 to 3.00; P = .028) progressed to dementia more rapidly than noncarriers.

Discussion: GBA variants are of great clinical relevance for the development of dementia in Parkinson's disease, especially due to the relatively higher frequency of these alleles compared with other risk alleles.

Keywords: GBA; Genetic association; Longitudinal; Parkinson's disease; Parkinson's disease with dementia.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Dementia / enzymology
Dementia / epidemiology
Dementia / genetics*
Female
Follow-Up Studies
Genetic Predisposition to Disease*
Glucosylceramidase / genetics*
Heterozygote
Humans
Longitudinal Studies
Male
Mutation*
Parkinson Disease / enzymology
Parkinson Disease / epidemiology
Parkinson Disease / genetics*
Polymorphism, Genetic*
Survival Analysis

Substances

GBA protein, human
Glucosylceramidase

Abstract

Publication types

MeSH terms

Substances

Grants and funding