eprintid: 1437467 rev_number: 48 eprint_status: archive userid: 608 dir: disk0/01/43/74/67 datestamp: 2014-08-15 19:15:00 lastmod: 2021-09-19 23:34:23 status_changed: 2016-06-15 11:44:20 type: article metadata_visibility: show item_issues_count: 0 creators_name: Sassi, C creators_name: Guerreiro, R creators_name: Gibbs, R creators_name: Ding, J creators_name: Lupton, MK creators_name: Troakes, C creators_name: Al-Sarraj, S creators_name: Niblock, M creators_name: Gallo, JM creators_name: Adnan, J creators_name: Killick, R creators_name: Brown, KS creators_name: Medway, C creators_name: Lord, J creators_name: Turton, J creators_name: Bras, J creators_name: Alzheimer's Research UK Consortium, creators_name: Morgan, K creators_name: Powell, JF creators_name: Singleton, A creators_name: Hardy, J 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 ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F86 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 note: Copyright © 2014 Elsevier Inc. Article available under CC BY licence 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. date: 2014-12 date_type: published official_url: http://dx.doi.org/10.1016/j.neurobiolaging.2014.06.002 vfaculties: VFBRS oa_status: green full_text_type: pub pmcid: PMC4236585 language: eng primo: open primo_central: open_green article_type_text: Journal Article verified: verified_manual elements_source: PubMed elements_id: 969333 doi: 10.1016/j.neurobiolaging.2014.06.002 pii: S0197-4580(14)00403-5 language_elements: eng lyricists_name: Hardy, John lyricists_name: Louro Guerreiro, Rita lyricists_name: Sassi, Celeste lyricists_name: Smalley, June lyricists_name: Tomas Bras, Jose lyricists_id: JHARD28 lyricists_id: RJLOU51 lyricists_id: CSASS81 lyricists_id: JASMA87 lyricists_id: JMTOM86 actors_name: Barczynska, Patrycja actors_id: PBARC91 actors_role: owner full_text_status: public publication: Neurobiology of Aging volume: 35 number: 12 pagerange: 2881.e1-2881.e6 event_location: United States issn: 1558-1497 citation: Sassi, C; Guerreiro, R; Gibbs, R; Ding, J; Lupton, MK; Troakes, C; Al-Sarraj, S; ... Hardy, J; + view all <#> Sassi, C; Guerreiro, R; Gibbs, R; Ding, J; Lupton, MK; Troakes, C; Al-Sarraj, S; Niblock, M; Gallo, JM; Adnan, J; Killick, R; Brown, KS; Medway, C; Lord, J; Turton, J; Bras, J; Alzheimer's Research UK Consortium; Morgan, K; Powell, JF; Singleton, A; Hardy, J; - view fewer <#> (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 <https://doi.org/10.1016/j.neurobiolaging.2014.06.002>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1437467/1/1-s2.0-S0197458014004035-main.pdf