Investigating the role of rare coding variability in Mendelian dementia genes ( APP , PSEN1 , PSEN2 , GRN , MAPT , and PRNP ) in late-onset Alzheimer's disease
Year: 2014
Type: article
Study design: Observational Study
Abstract: The overlapping clinical and neuropathologic features between late-onset apparently sporadic Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and other neurodegenerative dementias (frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jakob disease) raise the question of whether shared genetic risk factors may explain the similar phenotype among these disparate disorders. To investigate this intriguing hypothesis, we analyzed rare coding variability in 6 Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP), in 141 LOAD patients and 179 elderly controls, neuropathologically proven, from the UK. In our cohort, 14 LOAD cases (10%) and 11 controls (6%) carry at least 1 rare variant in the genes studied. We report a novel variant in PSEN1 (p.I168T) and a rare variant in PSEN2 (p.A237V), absent in controls and both likely pathogenic. Our findings support previous studies, suggesting that (1) rare coding variability in PSEN1 and PSEN2 may influence the susceptibility for LOAD and (2) GRN, MAPT, and PRNP are not major contributors to LOAD. Thus, genetic screening is pivotal for the clinical differential diagnosis of these neurodegenerative dementias.
Source: Neurobiology of Aging
Authors: Celeste Sassi, Rita Guerreiro, Raphael Gibbs, Jinhui Ding, Michelle K. Lupton, Claire Troakes, Safa Al-Sarraj, Michael Niblock, Jean-Marc Gallo, Jihad Adnan, Richard Killick, Kristelle S. Brown, Christopher Medway, Jenny Lord, James Turton, Jose Bras, Kevin Morgan, John F. Powell, Andrew Singleton, John Hardy
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $2,588
Funders: U.S. Department of Health and Human Services, Alzheimer's Association, University of Dundee, Wellcome Trust, NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, National Institute for Health and Care Research, University College London, University of Sheffield, Alzheimer’s Research UK, National Institutes of Health, Medical Research Council, Menzies Centre for Australian Studies, King's College London, University of London, National Institute on Aging
Awards: G2845388095, Plasma AB as a Surrogate Genetic Marker for LOAD, G3036763132, A systematic investigation into the pathogenesis and course of Parkinson's syndrome, Alzheimers Disease Patient Registry, G4298864339, RNA processing proteins and neurodegeneration: exploring mechanisms and modelling disease., G6045168401, G6265045657, Genetic Analysis Of Alzheimer s Disease, G6720564865, G687379476, A systematic investigation into the pathogenesis and course of Parkinson's syndrome., G9000005508, Mayo Alzheimer's Disease Research Center
OpenAlex ID: W2146453228