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

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...

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Published in	Movement disorders Vol. 37; no. 5; pp. 1016 - 1027
Main Authors	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 A., Yarnall, Alison J., Williams‐Gray, Caroline H., Macleod, Angus D., Counsell, Carl E., Tysnes, Ole‐Bjørn, Alves, Guido, Maple‐Grødem, Jodi
Format	Journal Article
Language	English
Published	Hoboken, USA John Wiley & Sons, Inc 01.05.2022 Wiley Subscription Services, Inc
Subjects	anatomi APOE Apolipoprotein E Apolipoprotein E4 - genetics Apolipoproteins E - genetics Cognitive ability cognitive decline Cognitive Dysfunction - genetics Dementia Dementia - genetics Dementia disorders GBA Genetic diversity Genotypes Genotyping Glucosylceramidase Glucosylceramidase - genetics Human Anatomy Humans Movement disorders Mutation Mutation - genetics nanomaterial nanomaterials Neurodegenerative diseases Parkinson Disease - complications Parkinson Disease - genetics Parkinson Disease - psychology Parkinson's disease Patients Population studies Population-based studies Synuclein Tau protein dementia Parkinson's disease APOE cognitive decline GBA
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ISSN	0885-3185 1531-8257 1531-8257
DOI	10.1002/mds.28932

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Summary:	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
Bibliography:	This work was supported by the Research Council of Norway (287842). The CamPaIGN study has received funding from the Wellcome Trust, the Medical Research Council, the Patrick Berthoud Trust, and the NIHR Cambridge Biomedical Research Centre (BRC‐1215‐20014). The ICICLE‐PD study was funded by Parkinson's UK (J‐0802, G‐1301, G‐1507) and supported by the Lockhart Parkinson's Disease Research Fund, National Institute for Health Research (NIHR) Newcastle Biomedical Research Unit and Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The NYPUM study was supported by grants from the Swedish Medical Research Council, Erling‐Persson Foundation, the Swedish Brain Foundation (Hjärnfonden), Umeå University, Västerbotten County Council, King Gustaf V and Queen Victoria Freemason Foundation, Swedish Parkinson Foundation, Swedish Parkinson Research Foundation, Kempe Foundation, Swedish PD Association, the European Research Council, and the Knut and Alice Wallenberg Foundation. The Norwegian ParkWest study has received funding from the Research Council of Norway (177966), the Western Norway Regional Health Authority (911218), the Norwegian Parkinson's Research Foundation, and Rebergs Legacy. The PICNICS study was funded by the Cure Parkinson's Trust, the Van Geest Foundation, the Medical Research Council, Parkinson's UK, and the NIHR Cambridge Biomedical Research Centre (BRC‐1215‐20014). The PINE study was funded by Parkinson's UK (grant numbers G0502, G0914, and G1302), the Scottish Chief Scientist Office (CAF/12/05, PCL/17/10), Academy of Medical Sciences, NHS Grampian endowments, the BMA Doris Hillier award, RS Macdonald Trust, the BUPA Foundation, and SPRING. The PICC collaboration has been supported by The Chief Scientist Office of the Scottish Government (PCL/17/10), the Academy of Medical Sciences, Parkinson's UK (initial collaborator meeting) and the Norwegian Association for Public Health. C.R.S.'s work was supported by NIH grants NINDS/NIA R01NS115144, U01NS095736, U01NS100603, and the American Parkinson Disease Association Center for Advanced Parkinson Research. This research was funded in whole, or in part by the UKRI Medical Research Council [MR/R007446/1]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Funding agencies ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 I.D. designed and performed the statistical analysis. Author Roles A.A.S., K.F.P., M.C., D.B., L.F., C.T., S.W.R., G.H., G.L., C.R.S., R.A.L., A.J.Y., C.H.W.G., A.D.M., C.E.C., O.B.T., G.A., and J.M.G. collected and analysed data. A.A.S. and J.M.G. wrote the first draft of the manuscript that was critically read, revised, and approved by all authors. J.M.G. and G.A. assisted with study conception and design, and establishing and supervising the study. A.A.S. conceived and organized the study and designed and performed the statistical analysis.
ISSN:	0885-3185 1531-8257 1531-8257
DOI:	10.1002/mds.28932