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.
Bibliographical noteAcknowledgments: We would like to thank all participants, study personnel from each study, and funders of individual studies and of PICC. We would like to thank Artur Wozniak and Adrian Martin from the University of Aberdeen, Data Management Department, for help in developing the PICC database. We acknowledge the contributions of members of the individual study
groups as detailed below. Members of PICC Steering Group: Dr. Angus D. Macleod, Dr. Carl E. Counsell (Chair), University of Aberdeen, UK; Prof. Ole-Bjørn Tysnes, University of Bergen, Norway; Marta Camacho, Dr. Caroline WilliamsGray, University of Cambridge, UK; Dr. Rachael A. Lawson, Newcastle University, UK; Dr. Jodi Maple-Grødem, Prof. Guido Alves, Stavanger University Hospital, Norway; Prof. Lars Forgren, Umeå University, Sweden. CamPaIGN study: Roger A. Barker, Thomas Foltynie, Sarah L. Mason, Caroline H. Williams-Gray. ICICLE-PD Study: David Burn, Lynn Rochester, Alison J. Yarnall, Rachael A. Lawson, Gordon W. Duncan, Tien K. Khoo. NYPUM Study: Lars Forsgren, Jan Linder, Mona Edström, Jörgen Andersson, Linda Eriksson, David Bäckström, Gun-Marie Hariz, Magdalena Domellöf. ParkWest Study: ParkWest Principal investigators: Guido Alves (Norwegian Centre for Movement Disorders, Stavanger University Hospital) and Ole-Bjørn Tysnes (Haukeland University Hospital). Study personnel: Michaela Dreetz Gjerstad, Kenn Freddy Pedersen, Elin Bjelland Forsaa, Veslemøy Hamre Frantzen, Anita Laugaland, Jodi MapleGrødem, Johannes Lange, Karen Simonsen, Eldbjørg Fiske and Ingvild Dalen (Stavanger University Hospital); Bernd Müller, Geir Olve Skeie and Marit Renså (Haukeland University Hospital); Wenche Telstad, Aliaksei Labusau and Jane Kastet (Førde Hospital); Ineke HogenEsch, Marianne
Kjerandsen and Liv Kari Håland (Haugesund Hospital); Karen Herlofson, Solgunn Ongre, and Siri Bruun (Sørlandet Hospital Arendal). PICNICS study: Roger A. Barker, Marta Camacho, Gemma Cummins, Jonathan R. Evans, David P. Breen, Ruwani S. Wijeyekoon, Caroline H. Williams-Gray. PINE Study: Medical: Carl E. Counsell, Kate S. M. Taylor, Robert Caslake, Angus D. Macleod, David J. M. McGhee, Diane Swallow; Research nurse/assistant: Joanne Gordon, Clare Harris, Ann Hayman, Nicola Johannesson, Hazel Forbes; Data management: Valerie Angus, Alasdair Finlayson, David Dawson, Katie Wilde, David Ritchie, Artur Wozniak; Statisticians: Neil Scott, Shona Fielding; Radiology: Prof. Alison Murray; Pathology: Ishbel Gall, Dr. James MacKenzie, Prof. Colin Smith; Secretarial: Aileen Sylvester, Susan Mitchell, Pam Rebecca, Ann Christie, and Diane McCosh.
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.
- Parkinson disease
- cognitive decline
- Parkinson's disease
- Apolipoproteins E/genetics
- Apolipoprotein E4/genetics
- Cognitive Dysfunction/genetics
- Parkinson Disease/complications
- GLUCOCEREBROSIDASE MUTATIONS