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

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Szwedo, Aleksandra A 
Dalen, Ingvild 
Pedersen, Kenn Freddy 
Bäckström, David 


jats:titleAbstract</jats:title>jats:secjats:titleBackground</jats:title>jats:pCommon genetic variance in apolipoprotein E (jats:italicAPOE</jats:italic>), β‐glucocerebrosidase (jats:italicGBA</jats:italic>), microtubule‐associated protein tau (jats:italicMAPT</jats:italic>), and α‐synuclein (jats:italicSNCA</jats:italic>) has been linked to cognitive decline in Parkinson's disease (PD), although studies have yielded mixed results.</jats:p></jats:sec>jats:secjats:titleObjectives</jats:title>jats:pTo evaluate the effect of genetic variants in jats:italicAPOE</jats:italic>, jats:italicGBA</jats:italic>, jats:italicMAPT</jats:italic>, and jats:italicSNCA</jats:italic> on cognitive decline and risk of dementia in a pooled analysis of six longitudinal, non‐selective, population‐based cohorts of newly diagnosed PD patients.</jats:p></jats:sec>jats:secjats:titleMethods</jats:title>jats:p1002 <jats:styled-content style="fixed-case">PD</jats:styled-content> patients, followed for up to 10 years (median 7.2 years), were genotyped for at least one of <jats:styled-content style="fixed-case">jats:italicAPOE</jats:italic></jats:styled-content>‐ε4, <jats:styled-content style="fixed-case">jats:italicGBA</jats:italic></jats:styled-content> mutations, <jats:styled-content style="fixed-case">jats:italicMAPT</jats:italic> H1</jats:styled-content>/<jats:styled-content style="fixed-case">H2</jats:styled-content>, or <jats:styled-content style="fixed-case">jats:italicSNCA</jats:italic></jats:styled-content> rs356219. We evaluated the effect of genotype on the rate of cognitive decline (Mini‐Mental State Examanation, <jats:styled-content style="fixed-case">MMSE</jats:styled-content>) using linear mixed models and the development of dementia (diagnosed using standardized criteria) using Cox regression; multiple comparisons were accounted for using <jats:styled-content style="fixed-case">Benjamini−Hochberg</jats:styled-content> corrections.</jats:p></jats:sec>jats:secjats:titleResults</jats:title>jats:pCarriers of jats:italicAPOE</jats:italic>‐ε4 (n = 281, 29.7%) and jats:italicGBA</jats:italic> mutations (n = 100, 10.3%) had faster cognitive decline and were at higher risk of progression to dementia (jats:italicAPOE</jats:italic>‐ε4, HR 3.57, jats:italicP</jats:italic> < 0.001; jats:italicGBA</jats:italic> mutations, HR 1.76, jats:italicP</jats:italic> = 0.001) than non‐carriers. The risk of cognitive decline and dementia (HR 5.19, jats:italicP</jats:italic> < 0.001) was further increased in carriers of both risk genotypes (n = 23). No significant effects were observed for jats:italicMAPT</jats:italic> or jats:italicSNCA</jats:italic> rs356219.</jats:p></jats:sec>jats:secjats:titleConclusions</jats:title>jats:p<jats:styled-content style="fixed-case">jats:italicGBA</jats:italic></jats:styled-content> and <jats:styled-content style="fixed-case">jats:italicAPOE</jats:italic></jats:styled-content> genotyping could improve the prediction of cognitive decline in <jats:styled-content style="fixed-case">PD</jats:styled-content>, which is important to inform the clinical trial selection and potentially to enable personalized treatment © 2022 The Authors. jats:italicMovement Disorders</jats:italic> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society</jats:p></jats:sec>


Funder: Academy of Medical Sciences; Id:

Funder: American Parkinson Disease Association Center for Advanced Parkinson Research

Funder: BMA Doris Hillier award

Funder: Bupa Foundation; Id:

Funder: Cure Parkinson's Trust

Funder: Erling‐Persson Foundation

Funder: European Research Council; Id:

Funder: Hjärnfonden; Id:

Funder: John and Lucille Van Geest Foundation; Id:

Funder: Kempestiftelserna; Id:

Funder: Knut och Alice Wallenbergs Stiftelse; Id:

Funder: Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse; Id:

Funder: Lockhart Parkinson's Disease Research Fund

Funder: Medical Research Council; Id:

Funder: Medicinska Forskningdet

Funder: NIHR Newcastle Biomedical Research Unit and Centre

Funder: NHS Grampian endowments

Funder: Norwegian Health Association; Id:

Funder: Norwegian Parkinson's Research Foundation

Funder: Patrick Berthoud Trust

Funder: Rebergs Legacy

Funder: RS Macdonald Trust

Funder: SPRING; Id:

Funder: Swedish Parkinson Foundation

Funder: Umeå Universitet; Id:

Funder: Västerbotten Läns Landsting; Id:

Funder: Wellcome Trust; Id:


RESEARCH ARTICLE, RESEARCH ARTICLES, Parkinson's disease, dementia, cognitive decline, APOE, GBA

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Movement Disorders

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Helse Vest (911218)
National Institutes of Health (NINDS/NIA R01NS115144, U01NS095736, U01NS100603)
NIHR Cambridge Biomedical Research Centre (BRC‐1215‐20014)
Norges Forskningsrd (177966, 287842)
Parkinson's UK (G‐0502, G‐0914, G‐1301, G‐1302, G‐1507, J‐0802)
Scottish Chief Scientist Office (CAF/12/05, PCL/17/10)