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

Alzheimer’s Disease Neuroimaging Initiative (ADNI)

doi:10.1007/s00401-020-02138-6

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

Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Research output: Contribution to Journal › Article › Academic › peer-review

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 pTau₁₈₁, 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 pTau₁₈₁ levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau₁₈₁ 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.

Original language	English
Pages (from-to)	1025-1044
Number of pages	20
Journal	Acta Neuropathologica
Volume	139
Issue number	6
Early online date	12 Mar 2020
DOIs	https://doi.org/10.1007/s00401-020-02138-6
Publication status	Published - Jun 2020

Funding

Open Access funding provided by Projekt DEAL. This publication was funded in part by the German Federal Ministry of Education and Research (BMBF) (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, 01ET1006B). Analyses were also funded by the German Federal Ministry of Education and Research (BMBF 01EA1410A) within the project “Diet-Body-Brain: from epidemiology to evidence-based communication”. Part of the work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Part of the analysis was funded by the German Research Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. 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). Data collection and sharing for this project were funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; ElanPharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research and Development, LLC.; Johnson and Johnson Pharmaceutical Research and Development LLC.; Lumosity; Lundbeck; Merck and Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California. The Three-City Study genotyping and analysis was funded by the GENMED Labex, the Joint Programming Initiative on Neurodegenerative Diseases Research (JPND; PERADES project), the Institute Pasteur de Lille, the University of Lille, and the Nord-Pas de Calais Regional Council. This work also benefited from the Lille Métropole Communauté Urbaine Council, the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to Alzheimer’s disease). In addition, the Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. Additional funding for the 3C Study was also obtained from the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM “Cohortes et collections de données biologiques” programme. Lille Génopôle received an unconditional grant from Eisai. Fundacio ACE cohort receives support from the Innovative Medicines Initiative 2 Joint Undertaking which receives support from the European Union’s Horizon 2020 research and innovation programme (ADAPTED Grant No. 115975). A. Ruiz’s research is also supported by Instituto de Salud Carlos III (ISCIII) grants PI13/02434, PI16/01861, and PI19/01301. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-“Una manera de Hacer Europa”), by Fundación bancaria “La Caixa” and Grifols SA (GR@ACE project). For the Longitudinal Aging Study Amsterdam (LASA) supports was largely obtained from a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The data collection in 2012–2013 was financially supported by the Netherlands Organization for Scientific Research (NWO) in the framework of the project “New Cohorts of young old in the twenty-first century” (File Number 480-10-014). Genotyping using Axiom-NL array was financially supported by EMGO+ Research Institute. PL was supported by the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. JW is supported by an Ilídio Pinho professorship and iBiMED (UID/BIM/04501/2013), at the University of Aveiro, Portugal. JP was supported by a grant from the Swiss National Science Foundation (320030L_141179). All authors report no conflict of interest. Piotr Lewczuk received a consultation and/or lecture honoraria from IBL International, Fujirebio Europe, AJ Roboscreen, and Roche. Jens Wiltfang received honoraria for consulting activities, lectures or advisory board participation from Pfizer, Eli Lilly, Hoffmann-La-Roche, MSD Sharp + Dome, Janssen-Cilag GmbH, Immungenetics AG, Boehringer Ingelheim. Lutz Frölich received honoraria for consulting activities, lectures, or advisory board participation from Allergan, Eli Lilly, Avraham Pharmaceuticals, Axon Neuroscience, Axovant, Biogen, Boehringer Ingelheim, Eisai, Functional Neuromodulation, Lundbeck, MerckSharpe and Dohme, Novartis, Pfizer, Pharnext, Roche, Schwabe Pharma; he served on Data and Safety Monitoring boards or endpoint committees with Avraham Pharmaceuticals, Axon Neuroscience, Forschungszentrum Jülich, Novartis, Pharmatropix. Julius Popp received honoraria for consulting activities, lectures or advisory board participation from Fujirebio Europe, Ono Pharma, Eli Lilly, and Nestlé Institute of Health Sciences. Agustin Ruiz reports consulting Fees: Landsteiner Genmed, Grifols, Araclon biotech. And Lecture Fees: Araclon Biotech.PA reports personal fees from Servier, Total, Genoscreen, Takeda, and Foundation Alzheimer. Oliver Peters received research funding, consultancy fees, or speech honoraria from Axovant, Biogen, Genentech, Lilly, Lundbeck, Novartis, Pharmatrophix, Piramal, Probiodrug, Roche, Takeda, and TauRx Pharmaceuticals. Merce Boada receives fees or has received for consulting from Lab. Servier, Roche, Lilly, Avid, Bayer, Elan, Janssen, Neuroptix, and Sanofi. She receives or has received fees for lectures from Lilly, Nutricia, Roche, Schwabe, Araclon, Esteve, Grifols, Janssen, Novartis, Piramal, Pfizer-Wyett, and Servier. She receives fees for being part of the Advisory Board of Lilly and Schwabe. She reports grants/research funding from Abbvie, Araclon, Biogen Research Limited, Bioiberica, Grifols, Lilly, S.A, Merck Sharp and Dohme, Kyowa Hakko Kirin, Laboratorios Servier, Nutricia SRL, Oryzon Genomics, Piramal Imaging Limited, Roche Pharma SA, and Schwabe Farma iberica SLU, all outside the submitted work. She has not received personal compensations from these organizations.

Funders	Funder number
DOD ADNI
EADB
EMGO+ Research Institute
Euroimmun
GENMED Labex
German Federal Ministry of Education and Research
ISCIII-Subdirección General de Evaluación
JPND EADB	01ED1619A
JPco-fuND FP-829-029
Joint Programming Initiative on Neurodegenerative Diseases Research
Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care
Netherlands Organization for Scientific Research
Nord-Pas de Calais Regional Council
Nutricia SRL
Piramal Imaging Limited
Schwabe Farma iberica SLU
National Institutes of Health
U.S. Department of Defense	W81XWH-12-2-0012
National Institute on Aging	U01AG024904
National Institute of Biomedical Imaging and Bioengineering
Eli Lilly and Company
Genentech
Roche
GE Healthcare
F. Hoffmann-La Roche
Alzheimer's Disease Neuroimaging Initiative
Universidade de Aveiro
Merck Sharp and Dohme
Horizon 2020 Framework Programme	115372, 115975
European Federation of Pharmaceutical Industries and Associations	UID/BIM/04501/2013
DoD Alzheimer's Disease Neuroimaging Initiative
Johnson and Johnson Pharmaceutical Research and Development
Janssen Alzheimer Immunotherapy Research And Development
Université de Lille
Deutsche Forschungsgemeinschaft	RA 1971/6-1
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	320030L_141179
ZonMw	733051061
Bundesministerium für Bildung und Forschung	01GI0714, 01GI0713, 01GI0716, 01GI0429, 01GI0715, 01GI0710, 01GI0423, 01GI0434, 01GI0712, 01GI0711, 01GI0420, 01GI0431, 01GI0422, 01GI0433, 01GI0102, 01EA1410A, 01ET1006B
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	480-10-014
Kyowa Hakko Kirin
Instituto de Salud Carlos III	PI13/02434, PI16/01861, PI19/01301
Seventh Framework Programme
Fujirebio Europe
Oryzon Genomics
European Regional Development Fund
Innovative Medicines Initiative
Servier
Institute Pasteur De Lille
IXICO
Fundación Bancaria Ibercaja
Transition Therapeutics

Keywords

Alzheimer’s disease
Cognitive decline
Mild cognitive impairment
Phospholipase C gamma 2
PLCG2

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s00401-020-02138-6

Persistent URL (handle)

Persistent link

Cite this

@article{b93eef2473ee43b5a56243a7e87e00cc,

title = "PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment",

abstract = "A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer{\textquoteright}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 pTau181, total tau, and Aβ1-42 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 pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 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 Aβ1-42 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.",

keywords = "Alzheimer{\textquoteright}s disease, Cognitive decline, Mild cognitive impairment, Phospholipase C gamma 2, PLCG2",

author = "Luca Kleineidam and Vincent Chouraki and Tomasz Pr{\'o}chnicki and {van der Lee}, {Sven J.} and Laura Madrid-M{\'a}rquez and Holger Wagner-Thelen and Ilker Karaca and Leonie Weinhold and Steffen Wolfsgruber and Anne Boland and {Martino Adami}, {Pamela V.} and Piotr Lewczuk and Julius Popp and Frederic Brosseron and Jansen, {Iris E.} and Marc Hulsman and Johannes Kornhuber and Oliver Peters and Claudine Berr and Reinhard Heun and Lutz Fr{\"o}lich and Christophe Tzourio and Dartigues, {Jean Fran{\c c}ois} and Michael H{\"u}ll and Ana Espinosa and Isabel Hern{\'a}ndez and {de Rojas}, Itziar and Adelina Orellana and Sergi Valero and Najada Stringa and {van Schoor}, {Natasja M.} and Martijn Huisman and Philip Scheltens and Phillipe Amouyel and Alfredo Ramirez and Eckart R{\"u}ther and Deleuze, {Jean Francois} and Jens Wiltfang and Lluis Tarraga and Matthias Schmid and Martin Scherer and Steffi Riedel-Heller and Heneka, {Michael T.} and Philippe Amouyel and Frank Jessen and Merce Boada and Wolfgang Maier and Anja Schneider and Antonio Gonz{\'a}lez-P{\'e}rez and {van der Flier}, {Wiesje M.} and Michael Wagner and Lambert, {Jean Charles} and Henne Holstege and S{\'a}ez, {Mª ªE} and Eicke Latz and Agustin Ruiz and Alfredo Ramirez and {Alzheimer{\textquoteright}s Disease Neuroimaging Initiative (ADNI)}",

year = "2020",

month = jun,

doi = "10.1007/s00401-020-02138-6",

language = "English",

volume = "139",

pages = "1025--1044",

journal = "Acta Neuropathologica",

issn = "0001-6322",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "6",

}

TY - JOUR

T1 - PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment

AU - Kleineidam, Luca

AU - Chouraki, Vincent

AU - Próchnicki, Tomasz

AU - van der Lee, Sven J.

AU - Madrid-Márquez, Laura

AU - Wagner-Thelen, Holger

AU - Karaca, Ilker

AU - Weinhold, Leonie

AU - Wolfsgruber, Steffen

AU - Boland, Anne

AU - Martino Adami, Pamela V.

AU - Lewczuk, Piotr

AU - Popp, Julius

AU - Brosseron, Frederic

AU - Jansen, Iris E.

AU - Hulsman, Marc

AU - Kornhuber, Johannes

AU - Peters, Oliver

AU - Berr, Claudine

AU - Heun, Reinhard

AU - Frölich, Lutz

AU - Tzourio, Christophe

AU - Dartigues, Jean François

AU - Hüll, Michael

AU - Espinosa, Ana

AU - Hernández, Isabel

AU - de Rojas, Itziar

AU - Orellana, Adelina

AU - Valero, Sergi

AU - Stringa, Najada

AU - van Schoor, Natasja M.

AU - Huisman, Martijn

AU - Scheltens, Philip

AU - Amouyel, Phillipe

AU - Ramirez, Alfredo

AU - Rüther, Eckart

AU - Deleuze, Jean Francois

AU - Wiltfang, Jens

AU - Tarraga, Lluis

AU - Schmid, Matthias

AU - Scherer, Martin

AU - Riedel-Heller, Steffi

AU - Heneka, Michael T.

AU - Amouyel, Philippe

AU - Jessen, Frank

AU - Boada, Merce

AU - Maier, Wolfgang

AU - Schneider, Anja

AU - González-Pérez, Antonio

AU - van der Flier, Wiesje M.

AU - Wagner, Michael

AU - Lambert, Jean Charles

AU - Holstege, Henne

AU - Sáez, Mª ªE

AU - Latz, Eicke

AU - Ruiz, Agustin

AU - Ramirez, Alfredo

AU - Alzheimer’s Disease Neuroimaging Initiative (ADNI)

PY - 2020/6

Y1 - 2020/6

N2 - 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 pTau181, total tau, and Aβ1-42 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 pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 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 Aβ1-42 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.

AB - 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 pTau181, total tau, and Aβ1-42 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 pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 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 Aβ1-42 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.

KW - Alzheimer’s disease

KW - Cognitive decline

KW - Mild cognitive impairment

KW - Phospholipase C gamma 2

KW - PLCG2

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U2 - 10.1007/s00401-020-02138-6

DO - 10.1007/s00401-020-02138-6

M3 - Article

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SN - 0001-6322

VL - 139

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EP - 1044

JO - Acta Neuropathologica

JF - Acta Neuropathologica

IS - 6

ER -

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

Abstract

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Keywords

UN SDGs

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Longitudinal Aging Study Amsterdam

Cite this

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

Abstract

Funding

Keywords

UN SDGs

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Datasets

Longitudinal Aging Study Amsterdam

Cite this