Progranulin mutations in clinical and neuropathological Alzheimer's disease
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...
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| Published in | Alzheimer's & dementia Vol. 18; no. 12; pp. 2458 - 2467 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
John Wiley and Sons Inc
01.12.2022
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| Subjects | |
| Online Access | Get full text |
| ISSN | 1552-5260 1552-5279 1552-5279 |
| DOI | 10.1002/alz.12567 |
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| 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. |
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| AbstractList | Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP-43 pathology.
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.
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.
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. Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP-43 pathology.INTRODUCTIONProgranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP-43 pathology.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.METHODSWe 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.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.RESULTSPathogenic 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.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.DISCUSSIONGRN 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. |
| Author | Schneider, Julie A. Wang, Li‐San Jiménez‐Velázquez, Ivonne Z. Farrer, Lindsay Bush, William Leung, Yuk Yee Bennett, David A. Reyes‐Dumeyer, Dolly Schellenberg, Gerard De Jager, Philip Haines, Jonathan L. Pericak‐Vance, Margaret A. Kukull, Walter Medrano, Martin Vardarajan, Badri N. Mayeux, Richard Piriz, Angel L. Martin, Eden Lantigua, Rafael A. Rivera, Diones |
| AuthorAffiliation | 14 Rush Alzheimer's Disease Center Rush University Medical Center Chicago Illinois USA 8 Department of Medicine University of Puerto Rico School of Medicine San Juan Puerto Rico USA 15 Department of Psychiatry 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 5 School of Medicine Pontificia Universidad Catolica Madre y Maestra (PUCMM) Santiago Dominican Republic 9 The John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Foundation Department of Human Genetics Miami Florida USA 12 School of Medicine University of Pennsylvania Philadelphia PA USA 4 Department of Medicine College of Physicians and Surgeons Columbia University, and the New York Presbyterian Hospital New York New York USA 7 School of Medi |
| AuthorAffiliation_xml | – name: 11 Boston University School of Medicine Boston Massachusetts USA – name: 6 Department of Neurology CEDIMAT, Plaza de la Salud Santo Domingo Dominican Republic – name: 9 The John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Foundation Department of Human Genetics Miami Florida USA – name: 13 Department of Epidemiology School of Public Health University of Washington Seattle Washington USA – name: 4 Department of Medicine College of Physicians and Surgeons Columbia University, and the New York Presbyterian Hospital New York New York USA – name: 15 Department of Psychiatry College of Physicians and Surgeons Columbia University New York New York USA – name: 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 – name: 7 School of Medicine Universidad Pedro Henriquez Urena (UNPHU) Santo Domingo Dominican Republic – name: 5 School of Medicine Pontificia Universidad Catolica Madre y Maestra (PUCMM) Santiago Dominican Republic – name: 10 Department of Biostatistics and Epidemiology Case Western Reserve University Cleveland Ohio USA – name: 2 The Gertrude H. Sergievsky Center College of Physicians and Surgeons Columbia University New York New York USA – name: 3 Department of Neurology College of Physicians and Surgeons Columbia University and the New York Presbyterian Hospital New York New York USA – name: 8 Department of Medicine University of Puerto Rico School of Medicine San Juan Puerto Rico USA – name: 12 School of Medicine University of Pennsylvania Philadelphia PA USA – name: 14 Rush Alzheimer's Disease Center Rush University Medical Center Chicago Illinois USA |
| Author_xml | – sequence: 1 givenname: Badri N. surname: Vardarajan fullname: Vardarajan, Badri N. email: bnv2103@cumc.columbia.edu organization: Columbia University and the New York Presbyterian Hospital – sequence: 2 givenname: Dolly surname: Reyes‐Dumeyer fullname: Reyes‐Dumeyer, Dolly organization: Columbia University and the New York Presbyterian Hospital – sequence: 3 givenname: Angel L. surname: Piriz fullname: Piriz, Angel L. organization: Columbia University – sequence: 4 givenname: Rafael A. surname: Lantigua fullname: Lantigua, Rafael A. organization: Columbia University, and the New York Presbyterian Hospital – sequence: 5 givenname: Martin surname: Medrano fullname: Medrano, Martin organization: Pontificia Universidad Catolica Madre y Maestra (PUCMM) – sequence: 6 givenname: Diones surname: Rivera fullname: Rivera, Diones organization: Universidad Pedro Henriquez Urena (UNPHU) – sequence: 7 givenname: Ivonne Z. surname: Jiménez‐Velázquez fullname: Jiménez‐Velázquez, Ivonne Z. organization: University of Puerto Rico School of Medicine – sequence: 8 givenname: Eden surname: Martin fullname: Martin, Eden organization: and Dr. John T. Macdonald Foundation Department of Human Genetics – sequence: 9 givenname: Margaret A. surname: Pericak‐Vance fullname: Pericak‐Vance, Margaret A. organization: and Dr. John T. Macdonald Foundation Department of Human Genetics – sequence: 10 givenname: William surname: Bush fullname: Bush, William organization: Case Western Reserve University – sequence: 11 givenname: Lindsay surname: Farrer fullname: Farrer, Lindsay organization: Boston University School of Medicine – sequence: 12 givenname: Jonathan L. surname: Haines fullname: Haines, Jonathan L. organization: Case Western Reserve University – sequence: 13 givenname: Li‐San surname: Wang fullname: Wang, Li‐San organization: University of Pennsylvania – sequence: 14 givenname: Yuk Yee surname: Leung fullname: Leung, Yuk Yee organization: University of Pennsylvania – sequence: 15 givenname: Gerard surname: Schellenberg fullname: Schellenberg, Gerard organization: University of Pennsylvania – sequence: 16 givenname: Walter surname: Kukull fullname: Kukull, Walter organization: University of Washington – sequence: 17 givenname: Philip surname: De Jager fullname: De Jager, Philip organization: Columbia University and the New York Presbyterian Hospital – sequence: 18 givenname: David A. surname: Bennett fullname: Bennett, David A. organization: Rush University Medical Center – sequence: 19 givenname: Julie A. surname: Schneider fullname: Schneider, Julie A. organization: Rush University Medical Center – sequence: 21 givenname: Richard surname: Mayeux fullname: Mayeux, Richard organization: Columbia University |
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| Snippet | Introduction
Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP‐43 pathology.... Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP-43 pathology. We determined the... Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP-43... |
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| SubjectTerms | Alzheimer Disease - genetics Alzheimer Disease - pathology Alzheimer's disease DNA-Binding Proteins - genetics Frontotemporal Lobar Degeneration - genetics Humans Intercellular Signaling Peptides and Proteins - genetics Mutation - genetics neuropathology progranulin Progranulins - genetics TDP43 |
| Title | Progranulin mutations in clinical and neuropathological Alzheimer's disease |
| URI | https://onlinelibrary.wiley.com/doi/abs/10.1002%2Falz.12567 https://www.ncbi.nlm.nih.gov/pubmed/35258170 https://www.proquest.com/docview/2637337216 https://pubmed.ncbi.nlm.nih.gov/PMC9360185 |
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