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1. PLD3 variants in population studies

Author

van der Lee, Sven J., Holstege, Henne, Wong, Tsz Hang, Jakobsdottir, Johanna, Bis, Joshua C., Chouraki, Vincent, van Rooij, Jeroen G. J., Grove, Megan L., Smith, Albert V., Amin, Najaf, Choi, Seung-Hoan, Beiser, Alexa S., Garcia, Melissa E., van IJcken, Wilfred F. J., Pijnenburg, Yolande A. L., Louwersheimer, Eva, Brouwer, Rutger W. W., van den Hout, Mirjam C. G. N., Oole, Edwin, Eirkisdottir, Gudny, Levy, Daniel, Rotter, Jerome I., Emilsson, Valur, OʼDonnell, Christopher J., Aspelund, Thor, Uitterlinden, Andre G., Launer, Lenore J., Hofman, Albert, Boerwinkle, Eric, Psaty, Bruce M., DeStefano, Anita L., Scheltens, Philip, Seshadri, Sudha, van Swieten, John C., Gudnason, Vilmundur, van der Flier, Wiesje M., Ikram, Arfan M., and van Duijn, Cornelia M.

Published
2015
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2. ABCA7 p.G215S as potential protective factor for Alzheimer's disease

Author

Passmore, Peter, Craig, David, Johnston, Janet, McGuinness, Bernadette, Todd, Stephen, Heun, Reinhard, Kölsch, Heike, Kehoe, Patrick G., Vardy, Emma R.L.C., Hooper, Nigel M., Mann, David M., Pickering-Brown, Stuart, Brown, Kristelle, Lowe, James, Morgan, Kevin, Smith, A. David, Wilcock, Gordon, Warden, Donald, Holmes, Clive, Sassi, Celeste, Nalls, Michael A., Ridge, Perry G., Gibbs, Jesse R., Ding, Jinhui, Lupton, Michelle K., Troakes, Claire, Lunnon, Katie, Al-Sarraj, Safa, Brown, Kristelle S., Medway, Christopher, Clement, Naomi, Lord, Jenny, Turton, James, Bras, Jose, Almeida, Maria R., Holstege, Henne, Louwersheimer, Eva, van der Flier, Wiesje M., Scheltens, Philip, Van Swieten, John C., Santana, Isabel, Oliveira, Catarina, Powell, John F., Kauwe, John S., Cruchaga, Carlos, Goate, Alison M., Singleton, Andrew B., Guerreiro, Rita, and Hardy, John

Published
2016
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3. SUCLG2 identified as both a determinator of CSF Aβ1–42 levels and an attenuator of cognitive decline in Alzheimerʼs disease

Author

Ramirez, Alfredo, van der Flier, Wiesje M., Herold, Christine, Ramonet, David, Heilmann, Stefanie, Lewczuk, Piotr, Popp, Julius, Lacour, André, Drichel, Dmitriy, Louwersheimer, Eva, Kummer, Markus P., Cruchaga, Carlos, Hoffmann, Per, Teunissen, Charlotte, Holstege, Henne, Kornhuber, Johannes, Peters, Oliver, Naj, Adam C., Chouraki, Vincent, Bellenguez, Céline, Gerrish, Amy, Heun, Reiner, Frölich, Lutz, Hüll, Michael, Buscemi, Lara, Herms, Stefan, Kölsch, Heike, Scheltens, Philip, Breteler, Monique M., Rüther, Eckart, Wiltfang, Jens, Goate, Alison, Jessen, Frank, Maier, Wolfgang, Heneka, Michael T., Becker, Tim, and Nöthen, Markus M.

Published
2014
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5. Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: A clinical interpretation strategy

Author

Holstege, H. (author), van der Lee, S.J. (author), Hulsman, M. (author), Hang Wong, Tsz (author), van Rooij, Jeroen G.J. (author), Weiss, Marjan (author), Louwersheimer, Eva (author), Wolters, Frank J, (author), Amin, Najaf (author), Reinders, M.J.T. (author), Holstege, H. (author), van der Lee, S.J. (author), Hulsman, M. (author), Hang Wong, Tsz (author), van Rooij, Jeroen G.J. (author), Weiss, Marjan (author), Louwersheimer, Eva (author), Wolters, Frank J, (author), Amin, Najaf (author), and Reinders, M.J.T. (author)

Abstract

Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1 variant pathogenicity. Findings were replicated in an independent sample of 103 SORL1 variants detected in 3193 AD cases and controls. In a combined sample of the discovery and replication samples, comprising 181 unique SORL1 variants, we developed a strategy to classify SORL1 variants into five subtypes ranging from pathogenic to benign. We tested this pathogenicity screen in SORL1 variants reported in two independent published studies. SORL1 variant pathogenicity is defined by the Combined Annotation Dependent Depletion (CADD) score and the minor allele frequency (MAF) reported by the Exome Aggregation Consortium (ExAC) database. Variants predicted strongly damaging (CADD score >30), which are extremely rare (ExAC-MAF <1 × 10 '5) increased AD risk by 12-fold (95% CI 4.2-34.3; P=5 × 10 '9). Protein-truncating SORL1 mutations were all unknown to ExAC and occurred exclusively in AD cases. More common SORL1 variants (ExAC-MAF≥1 × 10 '5) were not associated with increased AD risk, even when predicted strongly damaging. Findings were independent of gender and the APOE-I 4 allele. High-risk SORL1 variants were observed in a substantial proportion of the AD cases analyzed (2%). Based on their effect size, we propose to consider high-risk SORL1 variants next to variants in APOE, PSEN1, PSEN2 and APP for personalized risk assessments in clinical practice., Pattern Recognition and Bioinformatics

Published
2017
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6. Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease

Author

Schott, Jonathan M., Crutch, Sebastian J., Carrasquillo, Minerva M., Uphill, James, Shakespeare, Tim J., Ryan, Natalie S., Yong, Keir X., Lehmann, Manja, Ertekin-Taner, Nilufer, Graff-Radford, Neill R., Boeve, Bradley F., Murray, Melissa E., Khan, Qurat ul Ain, Petersen, Ronald C., Dickson, Dennis W., Knopman, David S., Rabinovici, Gil D., Miller, Bruce L., González, Aida Suárez, Gil-Néciga, Eulogio, Snowden, Julie S., Harris, Jenny, Pickering-Brown, Stuart M., Louwersheimer, Eva, van der Flier, Wiesje M., Scheltens, Philip, Pijnenburg, Yolande A., Galasko, Douglas, Sarazin, Marie, Dubois, Bruno, Magnin, Eloi, Galimberti, Daniela, Scarpini, Elio, Cappa, Stefano F., Hodges, John R., Halliday, Glenda M., Bartley, Lauren, Carrillo, Maria C., Bras, Jose T., Hardy, John, Rossor, Martin N., Collinge, John, Fox, Nick C., Mead, Simon, Department of Neurodegenerative Disease, Alzheimer Scotland Dementia Research Centre, Department of Neuroscience, Mayo Clinic Jacksonville, Department of Neurodegenerative Diseases, MRC Prion Unit, Department of Neurology, Mayo Clinic [Rochester], Cardiovascular Research Institute (UCSF), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Hospital Universitario Virgen del Rocío [Sevilla], Institute of Brain, Behaviour and Mental Health, University of Manchester [Manchester], Alzheimer center, VU University Medical Center [Amsterdam], Department of Epidemiology and biostatistics, School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), Neuro-anatomie fonctionnelle du comportement et de ses troubles, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre des Maladies Cognitives et Comportementales [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Mémoire de Ressources et de Recherche [CHRU de Besançon] (CMRR), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques [CHRU de Besançon], Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, University of New South Wales [Sydney] (UNSW), Alzheimer's Association, Department of Molecular Neurosciences, Institute of Neurology, UCL, University of California [San Francisco] (UCSF), University of California-University of California, UC San Diego School of Medicine, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Amsterdam Neuroscience - Neurodegeneration, Neurology, Epidemiology and Data Science, and HAL-UPMC, Gestionnaire

Subjects
Male, Epidemiology, Cell Adhesion Molecules, Neuronal, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Clinical Neurology, Selective vulnerability, Semaphorins, Polymorphism, Single Nucleotide, Cellular and Molecular Neuroscience, Apolipoproteins E, Developmental Neuroscience, Alzheimer Disease, Risk Factors, Mitochondrial Precursor Protein Import Complex Proteins, Genetics, GWAS, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Aged, Cerebral Cortex, Health Policy, Age Factors, Membrane Transport Proteins, Polynucleotide Adenylyltransferase, Proteins, Featured Article, Alzheimer's disease, Middle Aged, Psychiatry and Mental health, Posterior cortical atrophy, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Receptors, Complement 3b, Female, Geriatrics and Gerontology, Atrophy, APOE
Abstract

IntroductionThe genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain.MethodsWe genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome‐wide association study.ResultsWe confirm that variation in/near APOE/TOMM40 (P = 6 × 10−14) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10−4), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome‐wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10−10 OR = 1.9 [1.5–2.3]); rs72907046 near FAM46A (P = 1 × 10−9 OR = 3.2 [2.1–4.9]); and rs2525776 near SEMA3C (P = 1 × 10−8, OR = 3.3 [2.1–5.1]).DiscussionWe provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.

Published
2016

7. Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Alzheimer’s and Parkinson’s diseases

Author

Guerreiro, Rita, Escott-Price, Valentina, Darwent, Lee, Parkkinen, Laura, Ansorge, Olaf, Hernandez, Dena, Nalls, Michael A., Clark, Lorraine, Honig, Lawrence, Marder, Karen, Flier, Wiesje van der, Holstege, Henne, Louwersheimer, Eva, Lemstra, Afina, Scheltens, Philip, Barber, Imelda S., Braae, Anne, Brown, Kristelle, and Morgan, Kevin

Subjects
Genetic correlation, nervous system, Parkinson's disease, Dementia with Lewy bodies, mental disorders, Alzheimer's disease, behavioral disciplines and activities, nervous system diseases
Abstract

The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD.

Published
2016

8. ABCA7 p.G215S as potential protective factor for Alzheimer's disease

Author

Sassi, Celeste, Nalls, Michael A, Medway, Christopher, Clement, Naomi, Lord, Jenny, Turton, James, Bras, Jose, Almeida, Maria R, Consortium, ARUK, Holstege, Henne, Louwersheimer, Eva, van der Flier, Wiesje M, Ridge, Perry G, Scheltens, Philip, Van Swieten, John C, Santana, Isabel, Oliveira, Catarina, Morgan, Kevin, Powell, John F, Kauwe, John S, Cruchaga, Carlos, Goate, Alison M, Singleton, Andrew B, Gibbs, Jesse R, Guerreiro, Rita, Hardy, John, Passmore, Peter, Craig, David, Johnston, Janet, McGuinness, Bernadette, Todd, Stephen, Heun, Reinhard, Kölsch, Heike, Kehoe, Patrick G, Ding, Jinhui, Vardy, Emma R L C, Hooper, Nigel M, Mann, David M, Pickering-Brown, Stuart, Brown, Kristelle, Lowe, James, Smith, A David, Wilcock, Gordon, Warden, Donald, Lupton, Michelle K, Holmes, Clive, Troakes, Claire, Lunnon, Katie, Al-Sarraj, Safa, Brown, Kristelle S, Neurology, Human genetics, Amsterdam Neuroscience - Neurodegeneration, and Epidemiology and Data Science

Subjects
Adult, Male, Risk, ABCA7 protein, human, Protective variant, genetics [Alzheimer Disease], Genetic Reports Abstracts, ABCA7, Cohort Studies, Alzheimer Disease, Humans, Genetic Predisposition to Disease, ddc:610, genetics [Genetic Predisposition to Disease], Aged, Aged, 80 and over, Whole genome sequencing (WGS), Middle Aged, Genome-wide association studies (GWASs), Alzheimer's disease (AD), physiology [ATP-Binding Cassette Transporters], Female, ATP-Binding Cassette Transporters, genetics [ATP-Binding Cassette Transporters], Whole exome sequencing (WES), Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer's disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyze the single independent and joint effect of rare and low-frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, and CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North-American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low-frequency coding variant (p.G215S, rs72973581, minor allele frequency = 4.3%) conferring a modest but statistically significant protection against AD (p-value = 0.024, odds ratio = 0.57, 95% confidence interval = 0.41-0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provides new insights that should address functional studies.

Published
2016

9. Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy

Author

Holstege, Henne, primary, van der Lee, Sven J, additional, Hulsman, Marc, additional, Wong, Tsz Hang, additional, van Rooij, Jeroen GJ, additional, Weiss, Marjan, additional, Louwersheimer, Eva, additional, Wolters, Frank J, additional, Amin, Najaf, additional, Uitterlinden, André G, additional, Hofman, Albert, additional, Ikram, M Arfan, additional, van Swieten, John C, additional, Meijers-Heijboer, Hanne, additional, van der Flier, Wiesje M, additional, Reinders, Marcel JT, additional, van Duijn, Cornelia M, additional, and Scheltens, Philip, additional

Published
2017
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10. Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer’s Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity

Author

Louwersheimer, Eva, primary, Cohn-Hokke, Petra E., additional, Pijnenburg, Yolande A.L., additional, Weiss, Marjan M., additional, Sistermans, Erik A., additional, Rozemuller, Annemieke J., additional, Hulsman, Marc, additional, van Swieten, John C., additional, van Duijn, Cock M., additional, Barkhof, Frederik, additional, Koene, Teddy, additional, Scheltens, Philip, additional, Van der Flier, Wiesje M., additional, and Holstege, Henne, additional

Published
2017
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11. Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies

Author

Kun-Rodrigues, Celia, primary, Ross, Owen A., additional, Orme, Tatiana, additional, Shepherd, Claire, additional, Parkkinen, Laura, additional, Darwent, Lee, additional, Hernandez, Dena, additional, Ansorge, Olaf, additional, Clark, Lorraine N., additional, Honig, Lawrence S., additional, Marder, Karen, additional, Lemstra, Afina, additional, Scheltens, Philippe, additional, van der Flier, Wiesje, additional, Louwersheimer, Eva, additional, Holstege, Henne, additional, Rogaeva, Ekaterina, additional, St. George-Hyslop, Peter, additional, Londos, Elisabet, additional, Zetterberg, Henrik, additional, Barber, Imelda, additional, Braae, Anne, additional, Brown, Kristelle, additional, Morgan, Kevin, additional, Maetzler, Walter, additional, Berg, Daniela, additional, Troakes, Claire, additional, Al-Sarraj, Safa, additional, Lashley, Tammaryn, additional, Holton, Janice, additional, Compta, Yaroslau, additional, Van Deerlin, Vivianna, additional, Trojanowski, John Q., additional, Serrano, Geidy E., additional, Beach, Thomas G., additional, Clarimon, Jordi, additional, Lleó, Alberto, additional, Morenas-Rodríguez, Estrella, additional, Lesage, Suzanne, additional, Galasko, Douglas, additional, Masliah, Eliezer, additional, Santana, Isabel, additional, Diez, Monica, additional, Pastor, Pau, additional, Tienari, Pentti J., additional, Myllykangas, Liisa, additional, Oinas, Minna, additional, Revesz, Tamas, additional, Lees, Andrew, additional, Boeve, Brad F., additional, Petersen, Ronald C., additional, Ferman, Tanis J., additional, Escott-Price, Valentina, additional, Graff-Radford, Neill, additional, Cairns, Nigel J., additional, Morris, John C., additional, Stone, David J., additional, Pickering-Brown, Stuart, additional, Mann, David, additional, Dickson, Dennis W., additional, Halliday, Glenda M., additional, Singleton, Andrew, additional, Guerreiro, Rita, additional, and Bras, Jose, additional

Published
2017
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12. Alzheimer's disease risk variants modulate endophenotypes in mild cognitive impairment

Author

Louwersheimer, Eva, Wolfsgruber, Steffen, Espinosa, Ana, Lacour, Andre, Heilmann-Heimbach, Stefanie, Alegret, Montserrat, Hernandez, Isabel, Rosende-Roca, Maitee, Tarraga, Lluis, Boada, Merce, Kornhuber, Johannes, Peters, Oliver, Frolich, Lutz, Hull, Michael, Ruther, Eckart, Wiltfang, Jens, Scherer, Martin, Riedel-Heller, Steffi, Jessen, Frank, Nothen, Markus M., Maier, Wolfgang, Koene, Ted, Scheltens, Philip, Holstege, Henne, Wagner, Michael, Ruiz, Agustin, van der Flier, Wiesje M., Becker, Tim, Ramirez, Alfredo, Louwersheimer, Eva, Wolfsgruber, Steffen, Espinosa, Ana, Lacour, Andre, Heilmann-Heimbach, Stefanie, Alegret, Montserrat, Hernandez, Isabel, Rosende-Roca, Maitee, Tarraga, Lluis, Boada, Merce, Kornhuber, Johannes, Peters, Oliver, Frolich, Lutz, Hull, Michael, Ruther, Eckart, Wiltfang, Jens, Scherer, Martin, Riedel-Heller, Steffi, Jessen, Frank, Nothen, Markus M., Maier, Wolfgang, Koene, Ted, Scheltens, Philip, Holstege, Henne, Wagner, Michael, Ruiz, Agustin, van der Flier, Wiesje M., Becker, Tim, and Ramirez, Alfredo

Abstract

Introduction: We evaluated the effect of Alzheimer's disease (AD) susceptibility loci on endophenotypes closely related with AD pathology in patients with mild cognitive impairment (MCI). Methods: We selected 1730 MCI patients from four independent data sets. Weighted polygenic risk scores (PGS) were constructed of 18 non-apolipoprotein E (APOE) AD risk variants. In addition, we determined APOE genotype. AD endophenotypes were cognitive decline over time and cerebrospinal fluid (CSF) biomarkers (a beta, tau, ptau). Results: PGS was modestly associated with cognitive decline over time, as measured by mini-mental state examination (MMSE) (beta +/- SE: 0.24 +/- 0.10; P = .012), and with CSF levels of tau and ptau (tau: 1.38 +/- 0.36, P = 1.21 x 10(-4); ptau: 1.40 +/- 0.36, P = 1.02 x 10(-4)). Discussion: In MCI, we observed a joint effect of AD susceptibility loci on nonamyloid endophenotypes, suggesting a link of these genetic loci with neuronal degeneration in general rather than with Alzheimer-related amyloid deposition. (C) 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Published
2016

13. Heterogeneous Language Profiles in Patients with Primary Progressive Aphasia due to Alzheimer’s Disease

Author

Louwersheimer, Eva, primary, Keulen, M. Antoinette, additional, Steenwijk, Martijn D., additional, Wattjes, Mike P., additional, Jiskoot, Lize C., additional, Vrenken, Hugo, additional, Teunissen, Charlotte E., additional, van Berckel, Bart N.M., additional, van der Flier, Wiesje M., additional, Scheltens, Philip, additional, van Swieten, John C., additional, and Pijnenburg, Yolande A.L., additional

Published
2016
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14. Alzheimer's disease risk variants modulate endophenotypes in mild cognitive impairment

Author

Louwersheimer, Eva, primary, Wolfsgruber, Steffen, additional, Espinosa, Ana, additional, Lacour, André, additional, Heilmann‐Heimbach, Stefanie, additional, Alegret, Montserrat, additional, Hernández, Isabel, additional, Rosende‐Roca, Maitée, additional, Tárraga, Lluís, additional, Boada, Mercè, additional, Kornhuber, Johannes, additional, Peters, Oliver, additional, Frölich, Lutz, additional, Hüll, Michael, additional, Rüther, Eckart, additional, Wiltfang, Jens, additional, Scherer, Martin, additional, Riedel‐Heller, Steffi, additional, Jessen, Frank, additional, Nöthen, Markus M., additional, Maier, Wolfgang, additional, Koene, Ted, additional, Scheltens, Philip, additional, Holstege, Henne, additional, Wagner, Michael, additional, Ruiz, Agustín, additional, van der Flier, Wiesje M., additional, Becker, Tim, additional, and Ramirez, Alfredo, additional

Published
2016
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15. Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases

Author

Guerreiro, Rita, primary, Escott-Price, Valentina, additional, Darwent, Lee, additional, Parkkinen, Laura, additional, Ansorge, Olaf, additional, Hernandez, Dena G., additional, Nalls, Michael A., additional, Clark, Lorraine, additional, Honig, Lawrence, additional, Marder, Karen, additional, van der Flier, Wiesje, additional, Holstege, Henne, additional, Louwersheimer, Eva, additional, Lemstra, Afina, additional, Scheltens, Philip, additional, Rogaeva, Ekaterina, additional, St George-Hyslop, Peter, additional, Londos, Elisabet, additional, Zetterberg, Henrik, additional, Ortega-Cubero, Sara, additional, Pastor, Pau, additional, Ferman, Tanis J., additional, Graff-Radford, Neill R., additional, Ross, Owen A., additional, Barber, Imelda, additional, Braae, Anne, additional, Brown, Kristelle, additional, Morgan, Kevin, additional, Maetzler, Walter, additional, Berg, Daniela, additional, Troakes, Claire, additional, Al-Sarraj, Safa, additional, Lashley, Tammaryn, additional, Compta, Yaroslau, additional, Revesz, Tamas, additional, Lees, Andrew, additional, Cairns, Nigel J., additional, Halliday, Glenda M., additional, Mann, David, additional, Pickering-Brown, Stuart, additional, Powell, John, additional, Lunnon, Katie, additional, Lupton, Michelle K., additional, Dickson, Dennis, additional, Hardy, John, additional, Singleton, Andrew, additional, and Bras, Jose, additional

Published
2016
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16. F2-03-04: Genetic risk factors for posterior cortical atrophy

Author

Schott, Jonathan M., primary, Crutch, Sebastian J., additional, Carrasquillo, Minerva M., additional, Uphill, James, additional, Shakespeare, Tim J., additional, Ryan, Natalie S., additional, Lehmann, Manja, additional, Taner, Nilufer, additional, Graff-Radford, Neil, additional, Boeve, Bradley, additional, Murray, Melissa E., additional, Qurat ul Ain, Khan, additional, Petersen, Ronald C., additional, Dickson, Dennis W., additional, Knopman, David S., additional, Rabinovici, Gil D., additional, Gonzalez, Aida Suarez, additional, Gil-Néciga, Eulogio, additional, Snowden, Julie S., additional, Harris, Jenny, additional, Pickering-Brown, Stuart, additional, Louwersheimer, Eva, additional, van der Flier, Wiesje M., additional, Scheltens, Philip, additional, Pijnenburg, Yolande A.L., additional, Galasko, Douglas, additional, Sarazin, Marie, additional, Dubois, Bruno, additional, Magnin, Eloi, additional, Galimberti, Daniela, additional, Scarpini, Elio, additional, Cappa, Stefano F., additional, Hodges, John R., additional, Halliday, Glenda M., additional, Bartley, Lauren, additional, Bras, Jose T., additional, Hardy, John, additional, Rossor, Martin N., additional, Collinge, John, additional, Fox, Nick C., additional, and Mead, Simon, additional

Published
2015
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17. O4-05-04: A four-center study on the effect of polygenic risk score on cerebrospinal fluid markers and memory decline in mild cognitive impairment patients

Author

Louwersheimer, Eva, primary, Wolfsgruber, Steffen, additional, Espinosa, Ana, additional, Lacour, Andre, additional, Heilman, Stefanie, additional, Alegret, Monserrat, additional, Hernandez, Isabel, additional, Rosende-Roca, Maitée, additional, Tarraga, Lluis, additional, Kornhuber, Johannes, additional, Peters, Oliver, additional, Frölich, Lutz, additional, Hüll, Michael, additional, Rüther, Eckhart, additional, Wiltfang, Jens, additional, Scherer, Martin, additional, Riedel-Heller, Steffi G., additional, Jessen, Frank, additional, Nöthen, Markus, additional, Maier, Wolfgang, additional, Koene, Ted, additional, Scheltens, Philip, additional, Holstege, Henne, additional, Wagner, Michael, additional, Ruiz, Agustín, additional, van der Flier, Wiesje M., additional, and Ramirez, Alfredo, additional

Published
2015
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19. Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy

Author

Holstege, Henne, van der Lee, Sven J, Hulsman, Marc, Wong, Tsz Hang, van Rooij, Jeroen GJ, Weiss, Marjan, Louwersheimer, Eva, Wolters, Frank J, Amin, Najaf, Uitterlinden, André G, Hofman, Albert, Ikram, M Arfan, van Swieten, John C, Meijers-Heijboer, Hanne, van der Flier, Wiesje M, Reinders, Marcel JT, van Duijn, Cornelia M, and Scheltens, Philip

Abstract

Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1 variant pathogenicity. Findings were replicated in an independent sample of 103 SORL1 variants detected in 3193 AD cases and controls. In a combined sample of the discovery and replication samples, comprising 181 unique SORL1 variants, we developed a strategy to classify SORL1 variants into five subtypes ranging from pathogenic to benign. We tested this pathogenicity screen in SORL1 variants reported in two independent published studies. SORL1 variant pathogenicity is defined by the Combined Annotation Dependent Depletion (CADD) score and the minor allele frequency (MAF) reported by the Exome Aggregation Consortium (ExAC) database. Variants predicted strongly damaging (CADD score >30), which are extremely rare (ExAC-MAF <1 × 10−5) increased AD risk by 12-fold (95% CI 4.2–34.3; P=5 × 10−9). Protein-truncating SORL1 mutations were all unknown to ExAC and occurred exclusively in AD cases. More common SORL1 variants (ExAC-MAF≥1 × 10−5) were not associated with increased AD risk, even when predicted strongly damaging. Findings were independent of gender and the APOE-ε4 allele. High-risk SORL1 variants were observed in a substantial proportion of the AD cases analyzed (2%). Based on their effect size, we propose to consider high-risk SORL1 variants next to variants in APOE, PSEN1, PSEN2 and APP for personalized risk assessments in clinical practice.

Published
2017
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22. SUCLG2 identified as both a determinator of CSF Aβ1-42 levels and an attenuator of cognitive decline in Alzheimer's disease

Author

Ramirez, Alfredo, van der Flier, Wiesje M., Herold, Christine, Ramonet, David, Heilmann, Stefanie, Lewczuk, Piotr, Popp, Julius, Lacour, André, Drichel, Dmitriy, Louwersheimer, Eva, Kummer, Markus P., Cruchaga, Carlos, Hoffmann, Per, Teunissen, Charlotte, Holstege, Henne, Kornhuber, Johannes, Peters, Oliver, Naj, Adam C., Chouraki, Vincent, Bellenguez, Céline, Gerrish, Amy, Heun, Reiner, Frölich, Lutz, Hüll, Michael, Buscemi, Lara, Herms, Stefan, Kölsch, Heike, Scheltens, Philip, Breteler, Monique M., Rüther, Eckart, Wiltfang, Jens, Goate, Alison, Jessen, Frank, Maier, Wolfgang, Heneka, Michael T., Becker, Tim, Nöthen, Markus M., Ramirez, Alfredo, van der Flier, Wiesje M., Herold, Christine, Ramonet, David, Heilmann, Stefanie, Lewczuk, Piotr, Popp, Julius, Lacour, André, Drichel, Dmitriy, Louwersheimer, Eva, Kummer, Markus P., Cruchaga, Carlos, Hoffmann, Per, Teunissen, Charlotte, Holstege, Henne, Kornhuber, Johannes, Peters, Oliver, Naj, Adam C., Chouraki, Vincent, Bellenguez, Céline, Gerrish, Amy, Heun, Reiner, Frölich, Lutz, Hüll, Michael, Buscemi, Lara, Herms, Stefan, Kölsch, Heike, Scheltens, Philip, Breteler, Monique M., Rüther, Eckart, Wiltfang, Jens, Goate, Alison, Jessen, Frank, Maier, Wolfgang, Heneka, Michael T., Becker, Tim, and Nöthen, Markus M.

Abstract

Cerebrospinal fluid amyloid-beta 1-42 (Aβ1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on Aβ1-42 and pTau181 in AD dementia patients followed by independent replication. An association was found between Aβ1-42 level and a single-nucleotide polymorphism in SUCLG2 (rs62256378) (P = 2.5×10−12). An interaction between APOE genotype and rs62256378 was detected (P = 9.5 × 10−5), with the strongest effect being observed in APOE-ε4 noncarriers. Clinically, rs62256378 was associated with rate of cognitive decline in AD dementia patients (P = 3.1 × 10−3). Functional microglia experiments showed that SUCLG2 was involved in clearance of Aβ1-42

23. Analysis of C9orf72 repeat expansions in a large international cohort of Dementia with Lewy Bodies

Author

Kun-Rodrigues, Celia, Ross, Owen A., Orme, Tatiana, Shepherd, Claire, Parkkinen, Laura, Darwent, Lee, Hernandez, Dena, Ansorge, Olaf, Clark, Lorraine N., Honig, Lawrence, Marder, Karen, Lemstra, Afina, Scheltens, Philip, Flier, Wiesje van der, Louwersheimer, Eva, Holstege, Henne, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Londos, Elisabet, Zetterberg, Henrik, Barber, Imelda S., Braae, Anne, Brown, Kristelle, Morgan, Kevin, Maetzler, Walter, Berg, Daniela, Troakes, C., Al-Sarraj, S., Lashley, Tammaryn, Holton, Janice, Compta, Yaroslau, Van Deerlin, Vivianna, Trojanowski, John Q., Serrano, Geidy E., Beach, Thomas G., Clarimon, Jordi, Lleo, Alberto, Morenas-Rodriguez, Estrella, Lesage, Suzanne, Galasko, Douglas, Masliah, Eliezer, Santana, Isabel, Diez, Monica, Pastor, Pau, Tienari, Pentti J., Myllykangas, Liisa, Oinas, Minna, Revesz, Tamas, Lees, Andrew, Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., Escott-Price, Valentina, Graff-Radford, Neill R., Cairns, Nigel, Morris, John C., Stone, David, Pickering-Brown, Stuart, Mann, David, Dickson, Dennis W., Halliday, Glenda M., Singleton, Andrew, Guerreiro, Rita, Bras, Jose, Kun-Rodrigues, Celia, Ross, Owen A., Orme, Tatiana, Shepherd, Claire, Parkkinen, Laura, Darwent, Lee, Hernandez, Dena, Ansorge, Olaf, Clark, Lorraine N., Honig, Lawrence, Marder, Karen, Lemstra, Afina, Scheltens, Philip, Flier, Wiesje van der, Louwersheimer, Eva, Holstege, Henne, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Londos, Elisabet, Zetterberg, Henrik, Barber, Imelda S., Braae, Anne, Brown, Kristelle, Morgan, Kevin, Maetzler, Walter, Berg, Daniela, Troakes, C., Al-Sarraj, S., Lashley, Tammaryn, Holton, Janice, Compta, Yaroslau, Van Deerlin, Vivianna, Trojanowski, John Q., Serrano, Geidy E., Beach, Thomas G., Clarimon, Jordi, Lleo, Alberto, Morenas-Rodriguez, Estrella, Lesage, Suzanne, Galasko, Douglas, Masliah, Eliezer, Santana, Isabel, Diez, Monica, Pastor, Pau, Tienari, Pentti J., Myllykangas, Liisa, Oinas, Minna, Revesz, Tamas, Lees, Andrew, Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., Escott-Price, Valentina, Graff-Radford, Neill R., Cairns, Nigel, Morris, John C., Stone, David, Pickering-Brown, Stuart, Mann, David, Dickson, Dennis W., Halliday, Glenda M., Singleton, Andrew, Guerreiro, Rita, and Bras, Jose

Abstract

C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken in order to assess the role of C9orf72 repeat expansions in the disease. Here we investigated the prevalence of C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that C9orf72 repeat expansions are not causally associated with DLB.

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24. Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Alzheimer’s and Parkinson’s diseases

Author

Guerreiro, Rita, Escott-Price, Valentina, Darwent, Lee, Parkkinen, Laura, Ansorge, Olaf, Hernandez, Dena, Nalls, Michael A., Clark, Lorraine, Honig, Lawrence, Marder, Karen, Flier, Wiesje van der, Holstege, Henne, Louwersheimer, Eva, Lemstra, Afina, Scheltens, Philip, Barber, Imelda S., Braae, Anne, Brown, Kristelle, Morgan, Kevin, Guerreiro, Rita, Escott-Price, Valentina, Darwent, Lee, Parkkinen, Laura, Ansorge, Olaf, Hernandez, Dena, Nalls, Michael A., Clark, Lorraine, Honig, Lawrence, Marder, Karen, Flier, Wiesje van der, Holstege, Henne, Louwersheimer, Eva, Lemstra, Afina, Scheltens, Philip, Barber, Imelda S., Braae, Anne, Brown, Kristelle, and Morgan, Kevin

Abstract

The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD.

Full Text
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25. Analysis of C9orf72 repeat expansions in a large international cohort of Dementia with Lewy Bodies

Author

Kun-Rodrigues, Celia, Ross, Owen A., Orme, Tatiana, Shepherd, Claire, Parkkinen, Laura, Darwent, Lee, Hernandez, Dena, Ansorge, Olaf, Clark, Lorraine N., Honig, Lawrence, Marder, Karen, Lemstra, Afina, Scheltens, Philip, Flier, Wiesje van der, Louwersheimer, Eva, Holstege, Henne, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Londos, Elisabet, Zetterberg, Henrik, Barber, Imelda S., Braae, Anne, Brown, Kristelle, Morgan, Kevin, Maetzler, Walter, Berg, Daniela, Troakes, C., Al-Sarraj, S., Lashley, Tammaryn, Holton, Janice, Compta, Yaroslau, Van Deerlin, Vivianna, Trojanowski, John Q., Serrano, Geidy E., Beach, Thomas G., Clarimon, Jordi, Lleo, Alberto, Morenas-Rodriguez, Estrella, Lesage, Suzanne, Galasko, Douglas, Masliah, Eliezer, Santana, Isabel, Diez, Monica, Pastor, Pau, Tienari, Pentti J., Myllykangas, Liisa, Oinas, Minna, Revesz, Tamas, Lees, Andrew, Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., Escott-Price, Valentina, Graff-Radford, Neill R., Cairns, Nigel, Morris, John C., Stone, David, Pickering-Brown, Stuart, Mann, David, Dickson, Dennis W., Halliday, Glenda M., Singleton, Andrew, Guerreiro, Rita, Bras, Jose, Kun-Rodrigues, Celia, Ross, Owen A., Orme, Tatiana, Shepherd, Claire, Parkkinen, Laura, Darwent, Lee, Hernandez, Dena, Ansorge, Olaf, Clark, Lorraine N., Honig, Lawrence, Marder, Karen, Lemstra, Afina, Scheltens, Philip, Flier, Wiesje van der, Louwersheimer, Eva, Holstege, Henne, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Londos, Elisabet, Zetterberg, Henrik, Barber, Imelda S., Braae, Anne, Brown, Kristelle, Morgan, Kevin, Maetzler, Walter, Berg, Daniela, Troakes, C., Al-Sarraj, S., Lashley, Tammaryn, Holton, Janice, Compta, Yaroslau, Van Deerlin, Vivianna, Trojanowski, John Q., Serrano, Geidy E., Beach, Thomas G., Clarimon, Jordi, Lleo, Alberto, Morenas-Rodriguez, Estrella, Lesage, Suzanne, Galasko, Douglas, Masliah, Eliezer, Santana, Isabel, Diez, Monica, Pastor, Pau, Tienari, Pentti J., Myllykangas, Liisa, Oinas, Minna, Revesz, Tamas, Lees, Andrew, Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., Escott-Price, Valentina, Graff-Radford, Neill R., Cairns, Nigel, Morris, John C., Stone, David, Pickering-Brown, Stuart, Mann, David, Dickson, Dennis W., Halliday, Glenda M., Singleton, Andrew, Guerreiro, Rita, and Bras, Jose

Abstract

C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken in order to assess the role of C9orf72 repeat expansions in the disease. Here we investigated the prevalence of C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that C9orf72 repeat expansions are not causally associated with DLB.

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26. Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Alzheimer’s and Parkinson’s diseases

Author

Guerreiro, Rita, Escott-Price, Valentina, Darwent, Lee, Parkkinen, Laura, Ansorge, Olaf, Hernandez, Dena, Nalls, Michael A., Clark, Lorraine, Honig, Lawrence, Marder, Karen, Flier, Wiesje van der, Holstege, Henne, Louwersheimer, Eva, Lemstra, Afina, Scheltens, Philip, Barber, Imelda S., Braae, Anne, Brown, Kristelle, Morgan, Kevin, Guerreiro, Rita, Escott-Price, Valentina, Darwent, Lee, Parkkinen, Laura, Ansorge, Olaf, Hernandez, Dena, Nalls, Michael A., Clark, Lorraine, Honig, Lawrence, Marder, Karen, Flier, Wiesje van der, Holstege, Henne, Louwersheimer, Eva, Lemstra, Afina, Scheltens, Philip, Barber, Imelda S., Braae, Anne, Brown, Kristelle, and Morgan, Kevin

Abstract

The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD.

Full Text
View/download PDF

27. Analysis of C9orf72 repeat expansions in a large international cohort of Dementia with Lewy Bodies

Author

Kun-Rodrigues, Celia, Ross, Owen A., Orme, Tatiana, Shepherd, Claire, Parkkinen, Laura, Darwent, Lee, Hernandez, Dena, Ansorge, Olaf, Clark, Lorraine N., Honig, Lawrence, Marder, Karen, Lemstra, Afina, Scheltens, Philip, Flier, Wiesje van der, Louwersheimer, Eva, Holstege, Henne, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Londos, Elisabet, Zetterberg, Henrik, Barber, Imelda S., Braae, Anne, Brown, Kristelle, Morgan, Kevin, Maetzler, Walter, Berg, Daniela, Troakes, C., Al-Sarraj, S., Lashley, Tammaryn, Holton, Janice, Compta, Yaroslau, Van Deerlin, Vivianna, Trojanowski, John Q., Serrano, Geidy E., Beach, Thomas G., Clarimon, Jordi, Lleo, Alberto, Morenas-Rodriguez, Estrella, Lesage, Suzanne, Galasko, Douglas, Masliah, Eliezer, Santana, Isabel, Diez, Monica, Pastor, Pau, Tienari, Pentti J., Myllykangas, Liisa, Oinas, Minna, Revesz, Tamas, Lees, Andrew, Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., Escott-Price, Valentina, Graff-Radford, Neill R., Cairns, Nigel, Morris, John C., Stone, David, Pickering-Brown, Stuart, Mann, David, Dickson, Dennis W., Halliday, Glenda M., Singleton, Andrew, Guerreiro, Rita, Bras, Jose, Kun-Rodrigues, Celia, Ross, Owen A., Orme, Tatiana, Shepherd, Claire, Parkkinen, Laura, Darwent, Lee, Hernandez, Dena, Ansorge, Olaf, Clark, Lorraine N., Honig, Lawrence, Marder, Karen, Lemstra, Afina, Scheltens, Philip, Flier, Wiesje van der, Louwersheimer, Eva, Holstege, Henne, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Londos, Elisabet, Zetterberg, Henrik, Barber, Imelda S., Braae, Anne, Brown, Kristelle, Morgan, Kevin, Maetzler, Walter, Berg, Daniela, Troakes, C., Al-Sarraj, S., Lashley, Tammaryn, Holton, Janice, Compta, Yaroslau, Van Deerlin, Vivianna, Trojanowski, John Q., Serrano, Geidy E., Beach, Thomas G., Clarimon, Jordi, Lleo, Alberto, Morenas-Rodriguez, Estrella, Lesage, Suzanne, Galasko, Douglas, Masliah, Eliezer, Santana, Isabel, Diez, Monica, Pastor, Pau, Tienari, Pentti J., Myllykangas, Liisa, Oinas, Minna, Revesz, Tamas, Lees, Andrew, Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., Escott-Price, Valentina, Graff-Radford, Neill R., Cairns, Nigel, Morris, John C., Stone, David, Pickering-Brown, Stuart, Mann, David, Dickson, Dennis W., Halliday, Glenda M., Singleton, Andrew, Guerreiro, Rita, and Bras, Jose

Abstract

C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken in order to assess the role of C9orf72 repeat expansions in the disease. Here we investigated the prevalence of C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that C9orf72 repeat expansions are not causally associated with DLB.

Full Text
View/download PDF

28. Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Alzheimer’s and Parkinson’s diseases

Author

Guerreiro, Rita, Escott-Price, Valentina, Darwent, Lee, Parkkinen, Laura, Ansorge, Olaf, Hernandez, Dena, Nalls, Michael A., Clark, Lorraine, Honig, Lawrence, Marder, Karen, Flier, Wiesje van der, Holstege, Henne, Louwersheimer, Eva, Lemstra, Afina, Scheltens, Philip, Barber, Imelda S., Braae, Anne, Brown, Kristelle, Morgan, Kevin, Guerreiro, Rita, Escott-Price, Valentina, Darwent, Lee, Parkkinen, Laura, Ansorge, Olaf, Hernandez, Dena, Nalls, Michael A., Clark, Lorraine, Honig, Lawrence, Marder, Karen, Flier, Wiesje van der, Holstege, Henne, Louwersheimer, Eva, Lemstra, Afina, Scheltens, Philip, Barber, Imelda S., Braae, Anne, Brown, Kristelle, and Morgan, Kevin

Abstract

The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD.

Full Text
View/download PDF

29. Analysis of C9orf72 repeat expansions in a large international cohort of Dementia with Lewy Bodies

Author

Kun-Rodrigues, Celia, Ross, Owen A., Orme, Tatiana, Shepherd, Claire, Parkkinen, Laura, Darwent, Lee, Hernandez, Dena, Ansorge, Olaf, Clark, Lorraine N., Honig, Lawrence, Marder, Karen, Lemstra, Afina, Scheltens, Philip, Flier, Wiesje van der, Louwersheimer, Eva, Holstege, Henne, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Londos, Elisabet, Zetterberg, Henrik, Barber, Imelda S., Braae, Anne, Brown, Kristelle, Morgan, Kevin, Maetzler, Walter, Berg, Daniela, Troakes, C., Al-Sarraj, S., Lashley, Tammaryn, Holton, Janice, Compta, Yaroslau, Van Deerlin, Vivianna, Trojanowski, John Q., Serrano, Geidy E., Beach, Thomas G., Clarimon, Jordi, Lleo, Alberto, Morenas-Rodriguez, Estrella, Lesage, Suzanne, Galasko, Douglas, Masliah, Eliezer, Santana, Isabel, Diez, Monica, Pastor, Pau, Tienari, Pentti J., Myllykangas, Liisa, Oinas, Minna, Revesz, Tamas, Lees, Andrew, Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., Escott-Price, Valentina, Graff-Radford, Neill R., Cairns, Nigel, Morris, John C., Stone, David, Pickering-Brown, Stuart, Mann, David, Dickson, Dennis W., Halliday, Glenda M., Singleton, Andrew, Guerreiro, Rita, Bras, Jose, Kun-Rodrigues, Celia, Ross, Owen A., Orme, Tatiana, Shepherd, Claire, Parkkinen, Laura, Darwent, Lee, Hernandez, Dena, Ansorge, Olaf, Clark, Lorraine N., Honig, Lawrence, Marder, Karen, Lemstra, Afina, Scheltens, Philip, Flier, Wiesje van der, Louwersheimer, Eva, Holstege, Henne, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Londos, Elisabet, Zetterberg, Henrik, Barber, Imelda S., Braae, Anne, Brown, Kristelle, Morgan, Kevin, Maetzler, Walter, Berg, Daniela, Troakes, C., Al-Sarraj, S., Lashley, Tammaryn, Holton, Janice, Compta, Yaroslau, Van Deerlin, Vivianna, Trojanowski, John Q., Serrano, Geidy E., Beach, Thomas G., Clarimon, Jordi, Lleo, Alberto, Morenas-Rodriguez, Estrella, Lesage, Suzanne, Galasko, Douglas, Masliah, Eliezer, Santana, Isabel, Diez, Monica, Pastor, Pau, Tienari, Pentti J., Myllykangas, Liisa, Oinas, Minna, Revesz, Tamas, Lees, Andrew, Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., Escott-Price, Valentina, Graff-Radford, Neill R., Cairns, Nigel, Morris, John C., Stone, David, Pickering-Brown, Stuart, Mann, David, Dickson, Dennis W., Halliday, Glenda M., Singleton, Andrew, Guerreiro, Rita, and Bras, Jose

Abstract

C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken in order to assess the role of C9orf72 repeat expansions in the disease. Here we investigated the prevalence of C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that C9orf72 repeat expansions are not causally associated with DLB.

Full Text
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30. Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Alzheimer’s and Parkinson’s diseases

Author

Guerreiro, Rita, Escott-Price, Valentina, Darwent, Lee, Parkkinen, Laura, Ansorge, Olaf, Hernandez, Dena, Nalls, Michael A., Clark, Lorraine, Honig, Lawrence, Marder, Karen, Flier, Wiesje van der, Holstege, Henne, Louwersheimer, Eva, Lemstra, Afina, Scheltens, Philip, Barber, Imelda S., Braae, Anne, Brown, Kristelle, Morgan, Kevin, Guerreiro, Rita, Escott-Price, Valentina, Darwent, Lee, Parkkinen, Laura, Ansorge, Olaf, Hernandez, Dena, Nalls, Michael A., Clark, Lorraine, Honig, Lawrence, Marder, Karen, Flier, Wiesje van der, Holstege, Henne, Louwersheimer, Eva, Lemstra, Afina, Scheltens, Philip, Barber, Imelda S., Braae, Anne, Brown, Kristelle, and Morgan, Kevin

Abstract

The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD.

Full Text
View/download PDF

31. Analysis of C9orf72 repeat expansions in a large international cohort of Dementia with Lewy Bodies

Author

Kun-Rodrigues, Celia, Ross, Owen A., Orme, Tatiana, Shepherd, Claire, Parkkinen, Laura, Darwent, Lee, Hernandez, Dena, Ansorge, Olaf, Clark, Lorraine N., Honig, Lawrence, Marder, Karen, Lemstra, Afina, Scheltens, Philip, Flier, Wiesje van der, Louwersheimer, Eva, Holstege, Henne, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Londos, Elisabet, Zetterberg, Henrik, Barber, Imelda S., Braae, Anne, Brown, Kristelle, Morgan, Kevin, Maetzler, Walter, Berg, Daniela, Troakes, C., Al-Sarraj, S., Lashley, Tammaryn, Holton, Janice, Compta, Yaroslau, Van Deerlin, Vivianna, Trojanowski, John Q., Serrano, Geidy E., Beach, Thomas G., Clarimon, Jordi, Lleo, Alberto, Morenas-Rodriguez, Estrella, Lesage, Suzanne, Galasko, Douglas, Masliah, Eliezer, Santana, Isabel, Diez, Monica, Pastor, Pau, Tienari, Pentti J., Myllykangas, Liisa, Oinas, Minna, Revesz, Tamas, Lees, Andrew, Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., Escott-Price, Valentina, Graff-Radford, Neill R., Cairns, Nigel, Morris, John C., Stone, David, Pickering-Brown, Stuart, Mann, David, Dickson, Dennis W., Halliday, Glenda M., Singleton, Andrew, Guerreiro, Rita, Bras, Jose, Kun-Rodrigues, Celia, Ross, Owen A., Orme, Tatiana, Shepherd, Claire, Parkkinen, Laura, Darwent, Lee, Hernandez, Dena, Ansorge, Olaf, Clark, Lorraine N., Honig, Lawrence, Marder, Karen, Lemstra, Afina, Scheltens, Philip, Flier, Wiesje van der, Louwersheimer, Eva, Holstege, Henne, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Londos, Elisabet, Zetterberg, Henrik, Barber, Imelda S., Braae, Anne, Brown, Kristelle, Morgan, Kevin, Maetzler, Walter, Berg, Daniela, Troakes, C., Al-Sarraj, S., Lashley, Tammaryn, Holton, Janice, Compta, Yaroslau, Van Deerlin, Vivianna, Trojanowski, John Q., Serrano, Geidy E., Beach, Thomas G., Clarimon, Jordi, Lleo, Alberto, Morenas-Rodriguez, Estrella, Lesage, Suzanne, Galasko, Douglas, Masliah, Eliezer, Santana, Isabel, Diez, Monica, Pastor, Pau, Tienari, Pentti J., Myllykangas, Liisa, Oinas, Minna, Revesz, Tamas, Lees, Andrew, Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., Escott-Price, Valentina, Graff-Radford, Neill R., Cairns, Nigel, Morris, John C., Stone, David, Pickering-Brown, Stuart, Mann, David, Dickson, Dennis W., Halliday, Glenda M., Singleton, Andrew, Guerreiro, Rita, and Bras, Jose

Abstract

C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken in order to assess the role of C9orf72 repeat expansions in the disease. Here we investigated the prevalence of C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that C9orf72 repeat expansions are not causally associated with DLB.

Full Text
View/download PDF

32. Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Alzheimer’s and Parkinson’s diseases

Author

Guerreiro, Rita, Escott-Price, Valentina, Darwent, Lee, Parkkinen, Laura, Ansorge, Olaf, Hernandez, Dena, Nalls, Michael A., Clark, Lorraine, Honig, Lawrence, Marder, Karen, Flier, Wiesje van der, Holstege, Henne, Louwersheimer, Eva, Lemstra, Afina, Scheltens, Philip, Barber, Imelda S., Braae, Anne, Brown, Kristelle, Morgan, Kevin, Guerreiro, Rita, Escott-Price, Valentina, Darwent, Lee, Parkkinen, Laura, Ansorge, Olaf, Hernandez, Dena, Nalls, Michael A., Clark, Lorraine, Honig, Lawrence, Marder, Karen, Flier, Wiesje van der, Holstege, Henne, Louwersheimer, Eva, Lemstra, Afina, Scheltens, Philip, Barber, Imelda S., Braae, Anne, Brown, Kristelle, and Morgan, Kevin

Abstract

The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD.

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33. ABCA7 p.G215S as potential protective factor for Alzheimer's disease

Author

Sassi, Celeste, Nalls, Michael A., Ridge, Perry G., Gibbs, Jesse R., Ding, Jinhui, Lupton, Michelle K, Troakes, Claire, Lunnon, Katie, Al-Sarraj, Safa, Brown, Kristelle S, Medway, Christopher, Clement, Naomi, Lord, Jenny, Turton, James, Bras, Jose, Almeida, Maria R., Passmore, Peter, Craig, David, Johnston, Janet, McGuinness, Bernadette, Todd, Stephen, Heun, Reinhard, Kölsch, Heike, Kehoe, Patrick G, Vardy, Emma R L C, Hooper, Nigel M, Mann, David M., Pickering-Brown, Stuart, Lowe, James, Morgan, Kevin, Smith, A David, Wilcock, Gordon, Warden, Donald, Holmes, Clive, Holstege, Henne, Louwersheimer, Eva, van der Flier, Wiesje M., Scheltens, Philip, Van Swieten, John C., Santana, Isabel, Oliveira, Catarina, Powell, John F, Kauwe, John S K, Cruchaga, Carlos, Goate, Alison M, Singleton, Andrew B, Guerreiro, Rita, and Hardy, John

Subjects
Protective variant, Neuroscience(all), Clinical Neurology, Whole genome sequencing (WGS), Genome-wide association studies (GWASs), ABCA7, Ageing, Alzheimer's disease (AD), Geriatrics and Gerontology, Developmental Biology, Whole exome sequencing (WES)
Abstract

Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer's disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyze the single independent and joint effect of rare and low-frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, and CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North-American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low-frequency coding variant (p.G215S, rs72973581, minor allele frequency = 4.3%) conferring a modest but statistically significant protection against AD (p-value = 0.024, odds ratio = 0.57, 95% confidence interval = 0.41–0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provides new insights that should address functional studies.

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34. A four-center study on the effect of polygenic risk score on cerebrospinal fluid markers and memory decline in mild cognitive impairment patients.

Author

Louwersheimer, Eva, Wolfsgruber, Steffen, Espinosa, Ana, Lacour, Andre, Heilman, Stefanie, Alegret, Monserrat, Hernandez, Isabel, Rosende-Roca, Maitée, Tarraga, Lluis, Kornhuber, Johannes, Peters, Oliver, Frölich, Lutz, Hüll, Michael, Rüther, Eckhart, Wiltfang, Jens, Scherer, Martin, Riedel-Heller, Steffi G., Jessen, Frank, Nöthen, Markus, and Maier, Wolfgang

Published
2015
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35. ABCA7 p.G215S as potential protective factor for Alzheimer's disease.

Author

Sassi C, Nalls MA, Ridge PG, Gibbs JR, Ding J, Lupton MK, Troakes C, Lunnon K, Al-Sarraj S, Brown KS, Medway C, Clement N, Lord J, Turton J, Bras J, Almeida MR, Holstege H, Louwersheimer E, van der Flier WM, Scheltens P, Van Swieten JC, Santana I, Oliveira C, Morgan K, Powell JF, Kauwe JS, Cruchaga C, Goate AM, Singleton AB, Guerreiro R, and Hardy J

Subjects
Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Humans, Male, Middle Aged, Risk, ATP-Binding Cassette Transporters genetics, ATP-Binding Cassette Transporters physiology, Alzheimer Disease genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer's disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyze the single independent and joint effect of rare and low-frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, and CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North-American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low-frequency coding variant (p.G215S, rs72973581, minor allele frequency = 4.3%) conferring a modest but statistically significant protection against AD (p-value = 0.024, odds ratio = 0.57, 95% confidence interval = 0.41-0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provides new insights that should address functional studies., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2016
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36. Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease.

Author

Schott JM, Crutch SJ, Carrasquillo MM, Uphill J, Shakespeare TJ, Ryan NS, Yong KX, Lehmann M, Ertekin-Taner N, Graff-Radford NR, Boeve BF, Murray ME, Khan QU, Petersen RC, Dickson DW, Knopman DS, Rabinovici GD, Miller BL, González AS, Gil-Néciga E, Snowden JS, Harris J, Pickering-Brown SM, Louwersheimer E, van der Flier WM, Scheltens P, Pijnenburg YA, Galasko D, Sarazin M, Dubois B, Magnin E, Galimberti D, Scarpini E, Cappa SF, Hodges JR, Halliday GM, Bartley L, Carrillo MC, Bras JT, Hardy J, Rossor MN, Collinge J, Fox NC, and Mead S

Subjects
Age Factors, Aged, Alzheimer Disease complications, Apolipoproteins E genetics, Atrophy etiology, Female, Genetic Association Studies, Humans, Male, Membrane Transport Proteins genetics, Middle Aged, Mitochondrial Precursor Protein Import Complex Proteins, Polymorphism, Single Nucleotide genetics, Polynucleotide Adenylyltransferase, Receptors, Complement 3b genetics, Risk Factors, Alzheimer Disease genetics, Cell Adhesion Molecules, Neuronal genetics, Cerebral Cortex pathology, Genetic Predisposition to Disease genetics, Proteins genetics, Semaphorins genetics
Abstract

Introduction: The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain., Methods: We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study., Results: We confirm that variation in/near APOE/TOMM40 (P = 6 × 10(-14)) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10(-4)), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10(-10) OR = 1.9 [1.5-2.3]); rs72907046 near FAM46A (P = 1 × 10(-9) OR = 3.2 [2.1-4.9]); and rs2525776 near SEMA3C (P = 1 × 10(-8), OR = 3.3 [2.1-5.1])., Discussion: We provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2016
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37. Influence of genetic variants in SORL1 gene on the manifestation of Alzheimer's disease.

Author

Louwersheimer E, Ramirez A, Cruchaga C, Becker T, Kornhuber J, Peters O, Heilmann S, Wiltfang J, Jessen F, Visser PJ, Scheltens P, Pijnenburg YA, Teunissen CE, Barkhof F, van Swieten JC, Holstege H, and Van der Flier WM

Subjects
Aged, Aged, 80 and over, Alleles, Alzheimer Disease diagnosis, Alzheimer Disease pathology, Amides, Amyloid beta-Peptides cerebrospinal fluid, Biomarkers cerebrospinal fluid, Female, Hippocampus pathology, Humans, Male, Middle Aged, Phosphoric Acids, tau Proteins cerebrospinal fluid, Alzheimer Disease genetics, Genetic Association Studies, Genetic Predisposition to Disease genetics, LDL-Receptor Related Proteins genetics, Membrane Transport Proteins genetics, Polymorphism, Single Nucleotide genetics
Abstract

We studied the association of SORL1 single-nucleotide polymorphisms genotypes with measures of pathology in patients with probable Alzheimer's disease (AD) using an endophenotype approach. We included (1) 133 patients from the German Dementia Competence Network (71 ± 8 years; 50% females; Mini Mental State Examination [MMSE], 24 ± 3); (2) 83 patients from the Alzheimer's Disease Neuroimaging Initiative (75 ± 8 years; 45% females; MMSE, 24 ± 2); and (3) 452 patients from the Amsterdam Dementia Cohort 66 ± 8 years; 47% females; MMSE, 20 ± 5). As endophenotype markers we used cognitive tests, cerebrospinal fluid (CSF) biomarkers amyloid-beta, total tau (tau), tau phosphorylated at threonine 181, and hippocampal atrophy. We measured 19 SORL1 SNP alleles. Genotype-endophenotype associations were determined by linear regression analyses. There was an association between rs2070045-G allele and increased CSF-tau and more hippocampal atrophy. Additionally, haplotype-based analyses revealed an association between haplotype rs11218340-A/rs3824966-G/rs3824968-A and higher CSF-tau and CSF-tau phosphorylated at threonine 181. In conclusion, we found that SORL1 SNP rs2070045-G allele was related to CSF-tau and hippocampal atrophy, 2 endophenotype markers of AD, suggesting that SORL1 may be implicated in the downstream pathology in AD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Published
2015
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