Association between the LRP1B and APOE loci and the development of Parkinson’s disease dementia
Year: 2022
Type: review
Study design: Observational Study
Abstract: Parkinson's disease is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of Parkinson's disease, particularly in the later stages of the disease. However, the rate of cognitive decline varies among Parkinson's disease patients, and the genetic basis for this heterogeneity is incompletely understood. To explore the genetic factors associated with rate of progression to Parkinson's disease dementia, we performed a genome-wide survival meta-analysis of 3923 clinically diagnosed Parkinson's disease cases of European ancestry from four longitudinal cohorts. In total, 6.7% of individuals with Parkinson's disease developed dementia during study follow-up, on average 4.4 ± 2.4 years from disease diagnosis. We have identified the APOE ε4 allele as a major risk factor for the conversion to Parkinson's disease dementia [hazard ratio = 2.41 (1.94-3.00), P = 2.32 × 10-15], as well as a new locus within the ApoE and APP receptor LRP1B gene [hazard ratio = 3.23 (2.17-4.81), P = 7.07 × 10-09]. In a candidate gene analysis, GBA variants were also identified to be associated with higher risk of progression to dementia [hazard ratio = 2.02 (1.21-3.32), P = 0.007]. CSF biomarker analysis also implicated the amyloid pathway in Parkinson's disease dementia, with significantly reduced levels of amyloid β42 (P = 0.0012) in Parkinson's disease dementia compared to Parkinson's disease without dementia. These results identify a new candidate gene associated with faster conversion to dementia in Parkinson's disease and suggest that amyloid-targeting therapy may have a role in preventing Parkinson's disease dementia.
Source: Brain
Authors: Raquel Real, Alejandro Martinez-Carrasco, Regina H Reynolds, Michael A Lawton, Manuela M X Tan, Maryam Shoai, Jean-Christophe Corvol, Mina Ryten, Catherine Bresner, Leon Hubbard, Alexis Brice, Suzanne Lesage, Johann Faouzi, Alexis Elbaz, Fanny Artaud, Nigel Williams, Michele T M Hu, Yoav Ben-Shlomo, Donald G Grosset, John Hardy, Huw R Morris
Institutions: Aligning Science Across Parkinson's, UCL Queen Square Institute of Neurology, University College London, University of Bristol, Oslo University Hospital, UK Dementia Research Institute, Centre National de la Recherche Scientifique, Inserm, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Institut du Cerveau, UCL Biomedical Research Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Cardiff University, Centre Inria de Paris, Centre de recherche en Epidémiologie et Santé des Populations, University of Oxford, University of Glasgow, Hong Kong University of Science and Technology, National Institute for Health and Care Research
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,461
Funders: Foundation for the National Institutes of Health, Michael J. Fox Foundation for Parkinson's Research, Pfizer, Sanofi, Biogen, Celgene, Wellcome Trust, PSP Association, Alzheimer's Society, Verily Life Sciences, Aligning Science Across Parkinson’s, National Institute for Health and Care Research, Parkinson's UK, University College London, Agence Nationale de la Recherche, Edmond J. Safra Philanthropic Foundation, Association France Parkinson, Servier, H. Lundbeck A/S, Idorsia Pharmaceuticals, UK Dementia Research Institute, National Institutes of Health, Medical Research Council, Economic and Social Research Council, National Institute of Neurological Disorders and Stroke
OpenAlex ID: W4308571577