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

Sassi, C; Guerreiro, R; Gibbs, R; Ding, J; Lupton, MK; Troakes, C; Al-Sarraj, S; ... Hardy, J; + view all (2014) Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. Neurobiology of Aging , 35 (12) 2881.e1-2881.e6. 10.1016/j.neurobiolaging.2014.06.002. Green open access

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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.

Type: Article
Title: Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.neurobiolaging.2014.06.002
Publisher version: http://dx.doi.org/10.1016/j.neurobiolaging.2014.06...
Language: English
Additional information: Copyright © 2014 Elsevier Inc. Article available under CC BY licence
Keywords: APP, Alzheimer's disease, Exome sequencing, GRN, MAPT, Neurodegenerative dementia, PRNP, PSEN1, PSEN2, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Protein Precursor, Cohort Studies, Dementia, Diagnosis, Differential, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Humans, Intercellular Signaling Peptides and Proteins, Male, Middle Aged, Presenilin-1, Presenilin-2, Prions, tau Proteins
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/1437467
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