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

Aleksandra A Szwedo, Ingvild Dalen, Kenn Freddy Pedersen, Marta Camacho, David Bäckström, Lars Forsgren, Charalampos Tzoulis, Sophie Winder-Rhodes, Gavin Hudson, Ganqiang Liu, Clemens R Scherzer, Rachael A Lawson, Alison J Yarnall, Caroline H Williams-Gray, Angus D Macleod, Carl E Counsell, Ole-Bjørn Tysnes, Guido Alves, Jodi Maple-Grødem* (Corresponding Author), Parkinson’s Incidence Cohorts Collaboration

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

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.

Original languageEnglish
Pages (from-to)1016-1027
Number of pages12
JournalMovement Disorders
Volume37
Issue number5
Early online date2 Feb 2022
DOIs
Publication statusPublished - May 2022

Keywords

  • Parkinson disease
  • dementia
  • cognitive decline
  • APOE
  • GBA
  • Parkinson's disease
  • Apolipoproteins E/genetics
  • Mutation/genetics
  • Humans
  • Dementia/genetics
  • Apolipoprotein E4/genetics
  • Glucosylceramidase/genetics
  • Cognitive Dysfunction/genetics
  • Parkinson Disease/complications
  • MINI-MENTAL-STATE
  • DEMENTIA
  • SUSCEPTIBILITY
  • RISK
  • GLUCOCEREBROSIDASE MUTATIONS
  • POLYMORPHISMS
  • MOTOR
  • SCALE
  • ASSOCIATION
  • ONSET

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