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Start Over Author "Hernández, Isabel" Journal acta neuropathologica
5 results on '"Hernández, Isabel"'

1. Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Author

van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till FM, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart NM, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel JT, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande AL, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild IA, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, and Clarimón, Jordi

Subjects
DESGESCO, EADB, IFGC, IPDGC, RiMod-FTD, Netherlands Brain Bank, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Alzheimer's Disease, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Aging, Parkinson's Disease, Genetics, 2.1 Biological and endogenous factors, Neurological, Neurology & Neurosurgery, Clinical Sciences
Abstract

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.

Published
2020

2. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Author

van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till FM, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart NM, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank), EADB (Alzheimer Disease European DNA biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel JT, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande AL, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild IA, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, and Clarimón, Jordi

Subjects
DESGESCO (Dementia Genetics Spanish Consortium), EADB, EADB, IFGC (International FTD-Genomics Consortium), IPDGC, IPDGC, RiMod-FTD, Netherlands Brain Bank, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Alzheimer’s disease, Amyotrophic lateral sclerosis, Dementia with Lewy bodies, Frontotemporal dementia, Longevity, Multiple sclerosis, Neurodegenerative disease, PLCG2, Parkinson’s disease, Phospholipase C Gamma 2, Progressive supranuclear palsy, Alzheimer's disease, Parkinson's disease, Alzheimer's Disease, frontotemporal dementia, dementia with Lewy-bodies, progressive suprauclear palsy, Parkinson's Disease, amyotrophic lateral sclerosis, multiple sclerosis, neurodegenerative disease, longevity, Clinical Sciences, Neurosciences, Neurology & Neurosurgery
Abstract

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

Published
2019

3. Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers

Author

Jansen, Iris, van der Lee, Sven J, Bellenguez, Céline, Ramakers, Inez, Rodriguez-Rodriguez, Eloy, Rujescu, Dan, Saltvedt, Ingvild, Sanchez-Juan, Pascual, Scheltens, Philip, Scherbaum, Norbert, Schmid, Matthias, Schneider, Anja, Selbæk, Geir, Kleineidam, Luca, Selnes, Per, Shadrin, Alexey, Skoog, Ingmar, Soininen, Hilkka, Tárraga, Lluís, Teipel, Stefan, group, GR@ACE study, Tijms, Betty, Tsolaki, Magda, Van Broeckhoven, Christine, Küçükali, Fahri, Van Dongen, Jasper, van Swieten, John C, Vandenberghe, Rik, Vidal, Jean-Sébastien, Visser, Pieter J, Vogelgsang, Jonathan, Waern, Margda, Wagner, Michael, Wiltfang, Jens, Wittens, Mandy M J, Sung, Yun Ju, Zetterberg, Henrik, Zulaica, Miren, van Duijn, Cornelia M, Bjerke, Maria, Engelborghs, Sebastiaan, Jessen, Frank, Teunissen, Charlotte E, Pastor, Pau, Hiltunen, Mikko, Ingelsson, Martin, Tesí, Niccolo, Andreassen, Ole A, Clarimón, Jordi, Sleegers, Kristel, Ruiz, Agustín, Ramirez, Alfredo, Cruchaga, Carlos, Lambert, Jean-Charles, van der Flier, Wiesje, Vromen, Ellen M, Wightman, Douglas P, Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Gomez-Fonseca, Duber, Amouyel, Philippe, Athanasiu, Lavinia, Bahrami, Shahram, Bailly, Henri, Belbin, Olivia, Bergh, Sverre, Bertram, Lars, Biessels, Geert Jan, Blennow, Kaj, Blesa, Rafael, de Rojas, Itziar, Boada, Mercè, Boland, Anne, Bürger, Katharina, Carracedo, Ángel, Cervera-Carles, Laura, Chene, Geneviève, Claassen, Jurgen A H R, Debette, Stephanie, Deleuze, Jean-Francois, de Deyn, Peter Paul, Dalmasso, Maria Carolina, Diehl-Schmid, Janine, Djurovic, Srdjan, Dols-Icardo, Oriol, Dufouil, Carole, Duron, Emmanuelle, Düzel, Emrah, consortium, EADB, Fladby, Tormod, Fortea, Juan, Frölich, Lutz, Grenier-Boley, Benjamin, García-González, Pablo, Garcia-Martinez, Maria, Giegling, Ina, Goldhardt, Oliver, Gobom, Johan, Grimmer, Timo, Haapasalo, Annakaisa, Hampel, Harald, Hanon, Olivier, Hausner, Lucrezia, Zettergren, Anna, Heilmann-Heimbach, Stefanie, Helisalmi, Seppo, Heneka, Michael, Hernández, Isabel, Herukka, Sanna-Kaisa, Holstege, Henne, Jarholm, Jonas, Kern, Silke, Knapskog, Anne-Brita, Koivisto, Anne M, Mishra, Aniket, Kornhuber, Johannes, Kuulasmaa, Teemu, Lage, Carmen, Laske, Christoph, Leinonen, Ville, Lewczuk, Piotr, Lleó, Alberto, de Munain, Adolfo López, Lopez-Garcia, Sara, Maier, Wolfgang, Ali, Muhammad, Marquié, Marta, Mol, Merel O, Montrreal, Laura, Moreno, Fermin, Moreno-Grau, Sonia, Nicolas, Gael, Nöthen, Markus M, Orellana, Adelina, Pålhaugen, Lene, Papma, Janne M, Andrade, Victor, Pasquier, Florence, Perneczky, Robert, Peters, Oliver, Pijnenburg, Yolande A L, Popp, Julius, Posthuma, Danielle, Pozueta, Ana, Priller, Josef, Puerta, Raquel, Quintela, Inés, Molecular Neuroscience and Ageing Research (MOLAR), Complex Trait Genetics, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Complex Trait Genetics, VU University medical center, Neurology, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Brain Imaging, Laboratory Medicine, Amsterdam Neuroscience - Neuroinfection & -inflammation, APH - Personalized Medicine, APH - Methodology, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Psychology 2, Psychology 6, Pathologic Biochemistry and Physiology, Clinical Biology, Clinical sciences, Neuroprotection & Neuromodulation, European Commission, Clinical genetics, Amsterdam Reproduction & Development, Clinical chemistry, Department of Neurosciences, Clinicum, Helsinki University Hospital Area, University of Helsinki, HUS Neurocenter, Neurologian yksikkö, Epidemiology, and Universidad de Cantabria

Subjects
Neurologi, LD SCORE REGRESSION, Medizin, Cell Cycle Proteins, cerebrospinal fluid [Amyloid beta-Peptides], 3124 Neurology and psychiatry, pathology [Alzheimer Disease], Pathology, GWAS, RISK, NEURODEGENERATION, ASSOCIATION, Alzheimer's disease, AMYLOID-BETA, Cerebrospinal fluid, Neurology, cerebrospinal fluid [Biomarkers], Amyloid-beta, Life Sciences & Biomedicine, Alzheimer’s disease, EXPRESSION, Neuroscience(all), Clinical Neurology, tau Proteins, DIAGNOSIS, Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, Apolipoproteins E, SDG 3 - Good Health and Well-being, Alzheimer Disease, Humans, ddc:610, cerebrospinal fluid [Peptide Fragments], Amyloid beta-Peptides, Science & Technology, MUTATIONS, neurology, 3112 Neurosciences, Neurosciences, GENE, Peptide Fragments, genetics [tau Proteins], cerebrospinal fluid [tau Proteins], TAU LEVELS, genetics [Apolipoproteins E], 3111 Biomedicine, Human medicine, Neurology (clinical), Neurosciences & Neurology, Tau, Biomarkers
Abstract

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume. This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Programme, Neurodegenerative Disease Research (JPND). Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Part of the work described in this study was carried out in the context of the Parelsnoer Institute (PSI). PSI was part of and funded by the Dutch Federation of University Medical Centers and has received initial funding from the Dutch Government (from 2007-2011). Since 2020, this work was carried out in the context of Parelsnoer clinical biobanks at Health-RI (https://www.health-ri.nl/initiatives/parelsnoer).Part of the genotyping included in this work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Alfredo Ramirez is also supported by the German Research Foundation (DFG) grants Nr: RA 1971/6-1, RA1971/7-1, and RA 1971/8-1. We would like to thank patients and controls who participated in this project. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Grifols SA, Fundacion bancaria 'La Caixa', Fundacio ACE, and CIBERNED. A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de hacer Europa'). The position held by I.dR. is funded by grant. FI20/00215. PFIS Contratos Predoctorales de Formacion en Investigacion en Salud. We would like to thank UCL Genomics, London, UK, for performing the genotyping analyses of the samples within the Gothenburg H70 Birth Cohort Studies and Clinical AD Sweden. The recruitment and clinical characterization of research participants at Washington University were supported by NIH P30AG066444, and P01AG003991. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenom ics.wustl.edu/)and the Departments of Neurology and Psychiatry at Washington University School of Medicine. Research at the Belgian EADB site is funded in part by the Alzheimer Research Foundation (SAO-FRA), The Research Foundation Flanders (FWO), and the University of Antwerp Research Fund. FK is supported by a BOF DOCPRO fellowship of the University of Antwerp Research Fund. The work of Valdecilla was supported by grants from the Instituto de Salud Carlos III (Fondo de Investigacion Sanitario, PI08/0139, PI12/02288, PI16/01652, and PI20/01011), the JPND (DEMTEST PI11/03028), the CIBERNED, and the Siemens Healthineers. We thank the Valdecilla Biobank (PT17/0015/0019), integrated into the Spanish Biobank Network, for their support and collaboration in sample collection and management. Our heartfelt thanks to the participants of the Valdecilla Cohort for their generosity. The work of ADGEN was supported by EU Joint Programme-Neurodegenerative Disease Research (301220) and the Academy of Finland (338182). The DELCODE study (Study-ID:BN012) was supported and conducted by the German Center for Neurodegenerative Diseases (DZNE). The data samples were provided by the DELCODE study group. Details and participating sites can be found at www.dzne.de/en/research/studies/clinical-studies/delco de. The German Dementia Competence Network (KND) is funded by the German Federal Ministry of Education and Research (BMBF) grants Number: 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434, 01GI0711. WF, SvdL, HHolstege, CT and PhS are recipients of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and HealthHolland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD (www.aboard-project.nl).ABOARD also receives funding from de Hersenstichting, Edwin Bouw Fonds and Gieskes-Strijbisfonds. IEJ was partially supported by NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). AZ was supported by the Swedish Alzheimer Foundation (AF-939988, AF-930582, AF-646061, AF-741361), and the Dementia Foundation (2020-04-13, 2021-0417). ISk was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALFagreement (ALF 716681), the Swedish Research Council (no 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2019-01096), Swedish Research Council for Health, Working Life and Welfare (no 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 20050762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 20132496), Swedish Brain Power, Hjarnfonden, Sweden (FO2016-0214, FO2018-0214, FO2019-0163), the Alzheimer's Association Zenith Award (ZEN-01-3151), the Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159), the Alzheimer's Association (IIRG-03-6168, IIRG-09-131338) and the Bank of Sweden Tercentenary Foundation. SK was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-81392, ALF GBG-771071), the Swedish Alzheimer Foundation (AF-842471, AF-737641, AF-939825), and the Swedish Research Council (2019-02075). MW was supported by the Swedish Research Council 2016-01590. DP was supported by BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018-02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (2018092016862), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB was supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjarnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG06839801), and the Alzheimer's Association 2021 Zenith Award (ZEN-21848495). CC receives support from the National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG064614), and the Chuck Zuckerberg Initiative (CZI).

Published
2022

4. Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration

Author

van der Zee, Julie, primary, Van Langenhove, Tim, additional, Kovacs, Gabor G., additional, Dillen, Lubina, additional, Deschamps, William, additional, Engelborghs, Sebastiaan, additional, Matěj, Radoslav, additional, Vandenbulcke, Mathieu, additional, Sieben, Anne, additional, Dermaut, Bart, additional, Smets, Katrien, additional, Van Damme, Philip, additional, Merlin, Céline, additional, Laureys, Annelies, additional, Van Den Broeck, Marleen, additional, Mattheijssens, Maria, additional, Peeters, Karin, additional, Benussi, Luisa, additional, Binetti, Giuliano, additional, Ghidoni, Roberta, additional, Borroni, Barbara, additional, Padovani, Alessandro, additional, Archetti, Silvana, additional, Pastor, Pau, additional, Razquin, Cristina, additional, Ortega-Cubero, Sara, additional, Hernández, Isabel, additional, Boada, Mercè, additional, Ruiz, Agustín, additional, de Mendonça, Alexandre, additional, Miltenberger-Miltényi, Gabriel, additional, do Couto, Frederico Simões, additional, Sorbi, Sandro, additional, Nacmias, Benedetta, additional, Bagnoli, Silvia, additional, Graff, Caroline, additional, Chiang, Huei-Hsin, additional, Thonberg, Håkan, additional, Perneczky, Robert, additional, Diehl-Schmid, Janine, additional, Alexopoulos, Panagiotis, additional, Frisoni, Giovanni B., additional, Bonvicini, Christian, additional, Synofzik, Matthis, additional, Maetzler, Walter, additional, vom Hagen, Jennifer Müller, additional, Schöls, Ludger, additional, Haack, Tobias B., additional, Strom, Tim M., additional, Prokisch, Holger, additional, Dols-Icardo, Oriol, additional, Clarimón, Jordi, additional, Lleó, Alberto, additional, Santana, Isabel, additional, Almeida, Maria Rosário, additional, Santiago, Beatriz, additional, Heneka, Michael T., additional, Jessen, Frank, additional, Ramirez, Alfredo, additional, Sanchez-Valle, Raquel, additional, Llado, Albert, additional, Gelpi, Ellen, additional, Sarafov, Stayko, additional, Tournev, Ivailo, additional, Jordanova, Albena, additional, Parobkova, Eva, additional, Fabrizi, Gian Maria, additional, Testi, Silvia, additional, Salmon, Eric, additional, Ströbel, Thomas, additional, Santens, Patrick, additional, Robberecht, Wim, additional, De Jonghe, Peter, additional, Martin, Jean-Jacques, additional, Cras, Patrick, additional, Vandenberghe, Rik, additional, De Deyn, Peter Paul, additional, Cruts, Marc, additional, Sleegers, Kristel, additional, and Van Broeckhoven, Christine, additional

Published
2014
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5. PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment.

Author

Kleineidam L, Chouraki V, Próchnicki T, van der Lee SJ, Madrid-Márquez L, Wagner-Thelen H, Karaca I, Weinhold L, Wolfsgruber S, Boland A, Martino Adami PV, Lewczuk P, Popp J, Brosseron F, Jansen IE, Hulsman M, Kornhuber J, Peters O, Berr C, Heun R, Frölich L, Tzourio C, Dartigues JF, Hüll M, Espinosa A, Hernández I, de Rojas I, Orellana A, Valero S, Stringa N, van Schoor NM, Huisman M, Scheltens P, Rüther E, Deleuze JF, Wiltfang J, Tarraga L, Schmid M, Scherer M, Riedel-Heller S, Heneka MT, Amouyel P, Jessen F, Boada M, Maier W, Schneider A, González-Pérez A, van der Flier WM, Wagner M, Lambert JC, Holstege H, Sáez ME, Latz E, Ruiz A, and Ramirez A

Subjects
Aged, Aged, 80 and over, Alzheimer Disease genetics, Amyloid beta-Peptides genetics, Biomarkers analysis, Cognition physiology, Disease Progression, Female, Humans, Male, Middle Aged, tau Proteins cerebrospinal fluid, tau Proteins metabolism, Alzheimer Disease pathology, Cognitive Dysfunction genetics, Cognitive Dysfunction pathology, Phospholipase C gamma metabolism
Abstract

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau 181 , total tau, and Aβ 1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau 181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau 181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ 1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

Published
2020
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