Badri N Vardarajan1,2,3, Dolly Reyes-Dumeyer1,2,3, Angel L Piriz1,2, Rafael A Lantigua1,4, Martin Medrano5, Diones Rivera6,7, Ivonne Z Jiménez-Velázquez8, Eden Martin9, Margaret A Pericak-Vance9, William Bush10, Lindsay Farrer11, Jonathan L Haines10, Li-San Wang12, Yuk Yee Leung12, Gerard Schellenberg12, Walter Kukull13, Philip De Jager1,3, David A Bennett14, Julie A Schneider14, Richard Mayeux1,2,3,13,15. 1. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York, USA. 2. The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA. 3. Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, New York, USA. 4. Department of Medicine, College of Physicians and Surgeons, Columbia University, and the New York Presbyterian Hospital, New York, New York, USA. 5. School of Medicine, Pontificia Universidad Catolica Madre y Maestra (PUCMM), Santiago, Dominican Republic. 6. Department of Neurology, CEDIMAT, Plaza de la Salud, Santo Domingo, Dominican Republic. 7. School of Medicine, Universidad Pedro Henriquez Urena (UNPHU), Santo Domingo, Dominican Republic. 8. Department of Medicine, University of Puerto Rico School of Medicine, San Juan, Puerto Rico, USA. 9. The John P. Hussman Institute for Human Genomics, and Dr. John T. Macdonald Foundation Department of Human Genetics, Miami, Florida, USA. 10. Department of Biostatistics and Epidemiology, Case Western Reserve University, Cleveland, Ohio, USA. 11. Boston University School of Medicine, Boston, Massachusetts, USA. 12. School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 13. Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA. 14. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA. 15. Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Abstract
INTRODUCTION: Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP-43 pathology. METHODS: We determined the frequency of rs5848 and rare, pathogenic GRN mutations in two autopsy and one family cohort. We compared Braak stage, β-amyloid load, hyperphosphorylated tau (PHFtau) tangle density and TDP-43 pathology in GRN carriers and non-carriers. RESULTS: Pathogenic GRN mutations were more frequent in all cohorts compared to the Genome Aggregation Database (gnomAD), but there was no evidence for association with AD. Pathogenic GRN carriers had significantly higher PHFtau tangle density adjusting for age, sex and APOE ε4 genotype. AD patients with rs5848 had higher frequencies of hippocampal sclerosis and TDP-43 deposits. Twenty-two rare, pathogenic GRN variants were observed in the family cohort. DISCUSSION: GRN mutations in clinical and neuropathological AD increase the burden of tau-related brain pathology but show no specific association with β-amyloid load or AD.
INTRODUCTION: Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP-43 pathology. METHODS: We determined the frequency of rs5848 and rare, pathogenic GRN mutations in two autopsy and one family cohort. We compared Braak stage, β-amyloid load, hyperphosphorylated tau (PHFtau) tangle density and TDP-43 pathology in GRN carriers and non-carriers. RESULTS: Pathogenic GRN mutations were more frequent in all cohorts compared to the Genome Aggregation Database (gnomAD), but there was no evidence for association with AD. Pathogenic GRN carriers had significantly higher PHFtau tangle density adjusting for age, sex and APOE ε4 genotype. AD patients with rs5848 had higher frequencies of hippocampal sclerosis and TDP-43 deposits. Twenty-two rare, pathogenic GRN variants were observed in the family cohort. DISCUSSION: GRN mutations in clinical and neuropathological AD increase the burden of tau-related brain pathology but show no specific association with β-amyloid load or AD.
Authors: Gary W Beecham; J C Bis; E R Martin; S-H Choi; A L DeStefano; C M van Duijn; M Fornage; S B Gabriel; D C Koboldt; D E Larson; A C Naj; B M Psaty; W Salerno; W S Bush; T M Foroud; E Wijsman; L A Farrer; A Goate; J L Haines; Margaret A Pericak-Vance; E Boerwinkle; R Mayeux; S Seshadri; G Schellenberg Journal: Neurol Genet Date: 2017-10-13
Authors: David C Perry; Manja Lehmann; Jennifer S Yokoyama; Anna Karydas; Jason Jiyong Lee; Giovanni Coppola; Lea T Grinberg; Dan Geschwind; William W Seeley; Bruce L Miller; Howard Rosen; Gil Rabinovici Journal: JAMA Neurol Date: 2013-06 Impact factor: 18.302
Authors: Adam C Naj; Gyungah Jun; Gary W Beecham; Li-San Wang; Badri Narayan Vardarajan; Jacqueline Buros; Paul J Gallins; Joseph D Buxbaum; Gail P Jarvik; Paul K Crane; Eric B Larson; Thomas D Bird; Bradley F Boeve; Neill R Graff-Radford; Philip L De Jager; Denis Evans; Julie A Schneider; Minerva M Carrasquillo; Nilufer Ertekin-Taner; Steven G Younkin; Carlos Cruchaga; John S K Kauwe; Petra Nowotny; Patricia Kramer; John Hardy; Matthew J Huentelman; Amanda J Myers; Michael M Barmada; F Yesim Demirci; Clinton T Baldwin; Robert C Green; Ekaterina Rogaeva; Peter St George-Hyslop; Steven E Arnold; Robert Barber; Thomas Beach; Eileen H Bigio; James D Bowen; Adam Boxer; James R Burke; Nigel J Cairns; Chris S Carlson; Regina M Carney; Steven L Carroll; Helena C Chui; David G Clark; Jason Corneveaux; Carl W Cotman; Jeffrey L Cummings; Charles DeCarli; Steven T DeKosky; Ramon Diaz-Arrastia; Malcolm Dick; Dennis W Dickson; William G Ellis; Kelley M Faber; Kenneth B Fallon; Martin R Farlow; Steven Ferris; Matthew P Frosch; Douglas R Galasko; Mary Ganguli; Marla Gearing; Daniel H Geschwind; Bernardino Ghetti; John R Gilbert; Sid Gilman; Bruno Giordani; Jonathan D Glass; John H Growdon; Ronald L Hamilton; Lindy E Harrell; Elizabeth Head; Lawrence S Honig; Christine M Hulette; Bradley T Hyman; Gregory A Jicha; Lee-Way Jin; Nancy Johnson; Jason Karlawish; Anna Karydas; Jeffrey A Kaye; Ronald Kim; Edward H Koo; Neil W Kowall; James J Lah; Allan I Levey; Andrew P Lieberman; Oscar L Lopez; Wendy J Mack; Daniel C Marson; Frank Martiniuk; Deborah C Mash; Eliezer Masliah; Wayne C McCormick; Susan M McCurry; Andrew N McDavid; Ann C McKee; Marsel Mesulam; Bruce L Miller; Carol A Miller; Joshua W Miller; Joseph E Parisi; Daniel P Perl; Elaine Peskind; Ronald C Petersen; Wayne W Poon; Joseph F Quinn; Ruchita A Rajbhandary; Murray Raskind; Barry Reisberg; John M Ringman; Erik D Roberson; Roger N Rosenberg; Mary Sano; Lon S Schneider; William Seeley; Michael L Shelanski; Michael A Slifer; Charles D Smith; Joshua A Sonnen; Salvatore Spina; Robert A Stern; Rudolph E Tanzi; John Q Trojanowski; Juan C Troncoso; Vivianna M Van Deerlin; Harry V Vinters; Jean Paul Vonsattel; Sandra Weintraub; Kathleen A Welsh-Bohmer; Jennifer Williamson; Randall L Woltjer; Laura B Cantwell; Beth A Dombroski; Duane Beekly; Kathryn L Lunetta; Eden R Martin; M Ilyas Kamboh; Andrew J Saykin; Eric M Reiman; David A Bennett; John C Morris; Thomas J Montine; Alison M Goate; Deborah Blacker; Debby W Tsuang; Hakon Hakonarson; Walter A Kukull; Tatiana M Foroud; Jonathan L Haines; Richard Mayeux; Margaret A Pericak-Vance; Lindsay A Farrer; Gerard D Schellenberg Journal: Nat Genet Date: 2011-04-03 Impact factor: 38.330
Authors: S Sakura Minami; Sang-Won Min; Grietje Krabbe; Chao Wang; Yungui Zhou; Rustam Asgarov; Yaqiao Li; Lauren H Martens; Lisa P Elia; Michael E Ward; Lennart Mucke; Robert V Farese; Li Gan Journal: Nat Med Date: 2014-09-28 Impact factor: 53.440