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Neurobiol Aging. 2014 Dec;35(12):2881.e1-2881.e6. doi: 10.1016/j.neurobiolaging.2014.06.002. Epub 2014 Jun 16.

Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease.

Author information

1
Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. Electronic address: celeste.sassi.10@ucl.ac.uk.
2
Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
3
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
4
King's College London Institute of Psychiatry, London, UK.
5
Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
6
Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.

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.

KEYWORDS:

APP; Alzheimer's disease; Exome sequencing; GRN; MAPT; Neurodegenerative dementia; PRNP; PSEN1; PSEN2

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