Jon-Anders Tunold1,2, Hanneke Geut3, J M Annemieke Rozemuller4, Sandra Pilar Henriksen1, Mathias Toft1,2, Wilma D J van de Berg3, Lasse Pihlstrøm1. 1. Department of Neurology, Oslo University Hospital, Oslo, Norway. 2. Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 3. Section Clinical Neuroanatomy and Biobanking, Department of Anatomy and Neurosciences, Amsterdam UMC, Location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands. 4. Department of Pathology, Amsterdam UMC, Location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands.
Abstract
Introduction: Cognitive decline and dementia are common and debilitating non-motor phenotypic features of Parkinson's disease with a variable severity and time of onset. Common genetic variation of the Apolipoprotein E (APOE) and micro-tubule associated protein tau (MAPT) loci have been linked to cognitive decline and dementia in Parkinson's disease, although studies have yielded mixed results. To further elucidate the influence of APOE and MAPT variability on dementia in Parkinson's disease, we genotyped postmortem brain tissue samples of clinically and pathologically well-characterized Parkinson's donors and performed a survival analysis of time to dementia. Methods: We included a total of 152 neuropathologically confirmed Parkinson's disease donors with or without clinical dementia during life. We genotyped known risk variants tagging the APOE ε4 allele and MAPT H1/H2 inversion haplotype. Cox proportional hazards regression analyses adjusted for age at onset, sex and genetic principal components were performed to assess the association between the genetic variants and time from motor onset to onset of dementia. Results: We found that both the APOE ε4 allele (HR 1.82, 95 % CI 1.16-2.83, p = 0.009) and MAPT H1-haplotype (HR 1.71, 95 % CI 1.06-2.78, p = 0.03) were associated with earlier development of dementia in patients with Parkinson's disease. Conclusion: Our results provide further support for the importance of APOE ε4 and MAPT H1-haplotype in the etiology of Parkinson's disease dementia, with potential future relevance for risk stratification and patient selection for clinical trials of therapies targeting cognitive decline in Parkinson's disease.
Introduction: Cognitive decline and dementia are common and debilitating non-motor phenotypic features of Parkinson's disease with a variable severity and time of onset. Common genetic variation of the Apolipoprotein E (APOE) and micro-tubule associated protein tau (MAPT) loci have been linked to cognitive decline and dementia in Parkinson's disease, although studies have yielded mixed results. To further elucidate the influence of APOE and MAPT variability on dementia in Parkinson's disease, we genotyped postmortem brain tissue samples of clinically and pathologically well-characterized Parkinson's donors and performed a survival analysis of time to dementia. Methods: We included a total of 152 neuropathologically confirmed Parkinson's disease donors with or without clinical dementia during life. We genotyped known risk variants tagging the APOE ε4 allele and MAPT H1/H2 inversion haplotype. Cox proportional hazards regression analyses adjusted for age at onset, sex and genetic principal components were performed to assess the association between the genetic variants and time from motor onset to onset of dementia. Results: We found that both the APOE ε4 allele (HR 1.82, 95 % CI 1.16-2.83, p = 0.009) and MAPT H1-haplotype (HR 1.71, 95 % CI 1.06-2.78, p = 0.03) were associated with earlier development of dementia in patients with Parkinson's disease. Conclusion: Our results provide further support for the importance of APOE ε4 and MAPT H1-haplotype in the etiology of Parkinson's disease dementia, with potential future relevance for risk stratification and patient selection for clinical trials of therapies targeting cognitive decline in Parkinson's disease.
Authors: 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 Journal: Mov Disord Date: 2022-02-02 Impact factor: 9.698