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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
Open accessAbstract
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.
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In the citing paper
“PLCG2 polymorphisms are associated with both reduced and increased risk of Alzheimer’s disease (AD) and with longevity.”
From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [2]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The P522R variant in PLCG2 has been shown to confer protection for AD and to result in a subtle increase in enzymatic activity.”
From PLCγ2 regulates TREM2 signalling and integrin-mediated adhesion and migration of human iPSC-derived macrophages (2021) · cites this paper as [6]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“PLCG2 encodes Phospholipase C Gamma 2 (PLCγ2), which, upon activation by specific membrane receptors or Rac GTPases, enables hydrolysis of phosphatidylinositol (van der Lee et al. 2019; Kadamur and Ross 2013) bisphosphate (PI(4,5)P2) into diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (IP3).”
From Alzheimer's Protection by PLCγ2 Compacts Plaques, Redistributes Microglia, and Protects Synapses in App NL ‐G‐F Mice (2026) · cites this paper as van der Lee et al. 2019
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In contrast, the PLCγ2 variant had no protective effect on the risk of progressive supranuclear palsy, amyotrophic lateral sclerosis, Parkinson's disease, or multiple sclerosis (163).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [163]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“As a recent study on a centenarian cohort suggested, this variant could exert a beneficial effect on the entire immune system and promote healthy ageing [9], thus indicating that protection might also be mediated via the peripheral immune system, and could span the entire organism”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [9]
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“The mildly hypermorphic P522R variant (PLCG2P522R) is associated with resilience to AD as well as to other neurodegenerative disorders, including frontotemporal dementia and Lewy body dementia, 8 , 9”
From Alzheimer's disease–associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell–derived microglia‐like cells (2025) · cites this paper as [9]
The cited source says what the claim attributes to it.
In the citing paper
“On the other hand, three under-expressed pathways were related to aging, consistent with the previously reported association between PLCG2 and longevity(2).”
From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [2]
The cited source says what the claim attributes to it.
In the citing paper
“These include PLCG2 P522R rare variant (rs72824905) that provides robust protection against AD (odds ratio ≈ 0.68 [1, 4], comparable to having one APOE2 allele [5]”
From PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain (2026) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“Human genetic studies have identified a nonsynonymous PLCG2 variant (rs72824905-G) that confers reduced risk of AD, dementia with Lewy bodies, and frontotemporal dementia while increasing the likelihood of longevity, highlighting PLCG2 as a candidate therapeutic target [4].”
From PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain (2026) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“The missense variant P522R in PLCG2 (rs72824905-G, P = 5.38 × 10−10, OR = 0.68) was shown to be protective, not only in the context of AD4,5, but also in other neurodegenerative diseases such as frontotemporal dementia and dementia with Lewy bodies6.”
From PLCγ2 regulates TREM2 signalling and integrin-mediated adhesion and migration of human iPSC-derived macrophages (2021) · cites this paper as [6]
The cited source says what the claim attributes to it.
In the citing paper
“Genetic studies have identified a protective P522R variant in the PLCG2 gene (PLCG2-P522R; rs72824905 C > G), which decreases the risk of Alzheimer’s disease (AD) and increases longevity [1–4].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“Human studies confirmed the relevance of the R522 variant with other dementias and associated it with increased longevity in centenarian cohorts (Bellenguez et al. 2022; Conway et al. 2018; van der Lee et al. 2019).”
From Alzheimer's Protection by PLCγ2 Compacts Plaques, Redistributes Microglia, and Protects Synapses in App NL ‐G‐F Mice (2026) · cites this paper as van der Lee et al. 2019
The cited source says what the claim attributes to it.
In the citing paper
“Human studies confirmed the relevance of the R522 variant with other dementias and associated it with increased longevity in centenarian cohorts (Bellenguez et al. 2022; Conway et al. 2018; van der Lee et al. 2019).”
From Alzheimer's Protection by PLCγ2 Compacts Plaques, Redistributes Microglia, and Protects Synapses in App NL ‐G‐F Mice (2026) · cites this paper as van der Lee et al. 2019
The cited source says what the claim attributes to it.
In the citing paper
“Given the role for PLCγ2 in AD, we investigated how Plcg2 R522 expressing microglia altered amyloid‐driven pathology (Sims et al. 2017; Bellenguez et al. 2022; van der Lee et al. 2019).”
From Alzheimer's Protection by PLCγ2 Compacts Plaques, Redistributes Microglia, and Protects Synapses in App NL ‐G‐F Mice (2026) · cites this paper as van der Lee et al. 2019
The cited source says what the claim attributes to it.
In the citing paper
“the R522 variant of PLCγ2 is in humans associated with longevity and protection of cognitive function in old age and protects against AD, as well as frontotemporal dementia and dementia with Lewy bodies (Sims et al. 2017; van der Lee et al. 2019; Strickland et al. 2020).”
From Alzheimer's Protection by PLCγ2 Compacts Plaques, Redistributes Microglia, and Protects Synapses in App NL ‐G‐F Mice (2026) · cites this paper as van der Lee et al. 2019
The cited source says what the claim attributes to it.
In the citing paper
“Importantly, it has also been found that a rare variant of PLCγ2 (P522R) has a protective role in Alzheimer's disease (AD).”
From Characterisation of molecular mechanisms for PLCγ2 disease-linked variants (2024) · cites this paper as van der Lee et al., 2019
The cited source says what the claim attributes to it.
In the citing paper
“Recently, the reduced risk of the P522R mutation for AD has been extended to other dementia subtypes including Lewy bodies and frontotemporal dementia (163) (Fig. 4).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [163]
The cited source says what the claim attributes to it.
In the citing paper
“This variant was also associated with an increased chance of reaching at least 90 years of age and then becoming a cognitively healthy centenarian, that is, people in whom the absence of dementia and extreme longevity is combined (163).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [163]
The cited source says what the claim attributes to it.
In the citing paper
“and finally promotion of healthy ageing [1, 8, 9]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [9]
The cited source says what the claim attributes to it.
In the citing paper
“Moreover, the protective PLCγ2 variant seems to counteract the harmful effect of the APOE ε4 allele, as shown for a cognitively healthy centenarian carrying both the homozygous APOE ε4 and the PLCG2 protective polymorphism [9].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [9]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“other rare PLCG2 variants, such as M28L (rs61749044) that confers a modest increased risk of AD (OR ≈ 1.16) [1, 4, 7–13]”
From PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain (2026) · cites this paper as [4]
Experimental — accuracy not yet measuredIn the citing paper
“A non-synonymous coding variant in PCLG2, a gene with suspected immune function, has been associated with decreased risk of AD (van der Lee et al., 2019).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as van der Lee et al., 2019
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Metadata
- Authors
- DESGESCO (Dementia Genetics Spanish Consortium), E. (. D. E. D. B., van der Lee, S. J., biobank), E. (. D. E. D., IFGC (International FTD-Genomics Consortium), I. (. I. P. D. G. C., IPDGC (The International Parkinson Disease Genomics Consortium), Dementia), R.-F. (. A. M. F. I. F.-T., (NBB), N. B. B., The GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Conway, O. J., Jansen, I., Carrasquillo, M. M., Kleineidam, L., van den Akker, E., Hernández, I., van Eijk, K. R., Stringa, N., Chen, J. A., Zettergren, A., Andlauer, T. F. M., Diez-Fairen, M., Simon-Sanchez, J., Lleó, A., Zetterberg, H., Nygaard, M., Blauwendraat, C., Savage, J. E., Mengel-From, J., Moreno-Grau, S., Wagner, M., Fortea, J., Keogh, M. J., Blennow, K., Skoog, I., Friese, M. A., Pletnikova, O., Zulaica, M., Lage, C., de Rojas, I., Riedel-Heller, S., Illán-Gala, I., Wei, W., Jeune, B., Orellana, A., Then Bergh, F., Wang, X., Hulsman, M., Beker, N., Tesi, N., Morris, C. M., Indakoetxea, B., Collij, L. E., Scherer, M., Morenas-Rodríguez, E., Ironside, J. W., van Berckel, B. N. M., Alcolea, D., Wiendl, H., Strickland, S. L., Pastor, P., Rodríguez Rodríguez, E., Boeve, B. F., Petersen, R. C., Ferman, T. J., van Gerpen, J. A., Reinders, M. J. T., Uitti, R. J., Tárraga, L., Maier, W., Dols-Icardo, O., Kawalia, A., Dalmasso, M. C., Boada, M., Zettl, U. K., van Schoor, N. M., Beekman, M., Allen, M., Masliah, E., de Munain, A. L., Pantelyat, A., Wszolek, Z. K., Ross, O. A., Dickson, D. W., Graff-Radford, N. R., Knopman, D., Rademakers, R., Lemstra, A. W., Pijnenburg, Y. A. L., Scheltens, P., Gasser, T., Chinnery, P. F., Hemmer, B., Huisman, M. A., Troncoso, J., Moreno, F., Nohr, E. A., Sørensen, T. I. A., Heutink, P., Sánchez-Juan, P., Posthuma, D., Clarimón, J., Christensen, K., Ertekin-Taner, N., Scholz, S. W., Ramirez, A., Ruiz, A., Slagboom, E., van der Flier, W. M., & Holstege, H.
- Affiliations
- Mayo Clinic in Florida (US)
- Amsterdam Neuroscience (NL)
- University of Bonn (DE)
- Leiden University Medical Center (NL)
- Universitat Internacional de Catalunya (ES)
- University Medical Center Utrecht (NL)
- University Hospital Mútua de Terrassa (ES)
- University of California, Los Angeles (US)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Sahlgrenska University Hospital (SE)
- Universitat Autònoma de Barcelona (ES)
- University of Southern Denmark (DK)
- Johns Hopkins University (US)
- University of Cambridge (GB)
- Mayo Clinic (US)
- University of Cologne (DE)
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- National Institutes of Health (US)
- Hertie Institute for Clinical Brain Research (DE)
- Amsterdam Public Health (NL)
- Corresponding author
- Holstege, Henne
- ORCID
- van der Lee, Sven J.
- Jansen, Iris
- Carrasquillo, Minerva M.
- Kleineidam, Luca
- Stringa, Najada
- Chen, Jason A.
- Zettergren, Anna
- Andlauer, Till F. M.
- Lleó, Alberto
- Zetterberg, Henrik
- Nygaard, Marianne
- Blauwendraat, Cornelis
- Savage, Jeanne E.
- Wagner, Michael
- Fortea, Juan
- Keogh, Michael J.
- Blennow, Kaj
- Skoog, Ingmar
- Friese, Manuel A.
- Zulaica, Miren
- Lage, Carmen
- Riedel-Heller, Steffi
- Wei, Wei
- Jeune, Bernard
- Orellana, Adelina
- Wang, Xue
- Hulsman, Marc
- Beker, Nina
- Tesi, Niccolo
- Morris, Christopher M.
- Collij, Lyduine E.
- Scherer, Martin
- Ironside, James W.
- Alcolea, Daniel
- Wiendl, Heinz
- Strickland, Samantha L.
- Boeve, Bradley F.
- Petersen, Ronald C.
- Ferman, Tanis J.
- Reinders, Marcel J. T.
- Uitti, Ryan J.
- Tárraga, Lluís
- Maier, Wolfgang
- Kawalia, Amit
- Zettl, Uwe K.
- Beekman, Marian
- Allen, Mariet
- Masliah, Eliezer
- Pantelyat, Alexander
- Ross, Owen A.
- Dickson, Dennis W.
- Knopman, David
- Rademakers, Rosa
- Lemstra, Afina W.
- Pijnenburg, Yolande A. L.
- Scheltens, Philip
- Gasser, Thomas
- Chinnery, Patrick F
- Hemmer, Bernhard
- Huisman, Martijn A.
- Troncoso, Juan
- Nohr, Ellen A.
- Sørensen, Thorkild I. A.
- Heutink, Peter
- Clarimón, Jordi
- Christensen, Kaare
- Scholz, Sonja W.
- Holstege, Henne
- Venue
- Acta Neuropathologica
- Published
- 2019-05-26
- Volume
- 138
- Issue
- 2
- Pages
- 237-250
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC6660501
- OpenAlex
- W2944923405
- Cited by
- 120
- References
- 67
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 18 · 2023: 13 · 2022: 10 · 2021: 23 · 2020: 29 · 2019: 6
- FWCI
- 10.14
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-01-18)
- Open access
- hybrid
- doi.org
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- SSRN Electronic Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, cc-by)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- Explore Bristol Research (publishedVersion, cc-by)
- VU Research Portal (publishedVersion, other-oa)
- Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
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- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- DZNE Pub (submittedVersion, cc-by)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- UCrea (University of Cantabria) (submittedVersion, cc-by)
- Bristol Research (University of Bristol) (submittedVersion, cc-by)
- CONICET Digital (CONICET) (submittedVersion, cc-by)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by)
- Research Repository (Delft University of Technology) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Apollo (cc-by)
- Funders
- Mayo Clinic (P50 NS072187, U01 AG046139, R01 NS080820)
- Alzheimer's Association (ZEN‐01‐3151)
- Alexander von Humboldt-Stiftung
- American Parkinson Disease Association (R01 NS078086, P50 NS072187)
- University of Miami
- Johns Hopkins University (P50-AG005146, AG005146)
- Georgetown University
- CurePSP
- Virginia Commonwealth University
- Wellcome Trust (084762, 212219/Z/18/Z, WT084762)
- Little Family Foundation (P50 NS072187, R01 NS078086)
- Demensförbundet
- European Federation of Pharmaceutical Industries and Associations (115975)
- Sol Goldman Charitable Trust
- Lewy Body Dementia Association
- Motor Neurone Disease Association
- University College London
- ZonMw (733051061, 733050814)
- Bundesministerium für Bildung und Forschung (01GI0916, 01GI0917, 01ZX1614J)
- Generalitat de Catalunya (2017-SGR)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (050.060.810, 480- 05-003, 453-13-005, 453-14-005)
- Vetenskapsrådet (2013-2300, 2013‐2496, 2015-02830)
- Banco Bilbao Vizcaya Argentaria
- Sahlgrenska Universitetssjukhuset
- Stichting ALS Nederland
- Centre for Medical Systems Biology
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (PI13/02434, Program1, PI16/01861)
- Grifols
- National Institutes of Health (U19-AG03365, NIH P50, NS38377, AG046139, NS100693, NS072187, Z01-AG000949, P50 NS38377)
- Center for Individualized Medicine, Mayo Clinic
- Tau Consortium
- Medical Research Council (MC_UU_00015/7)
- Instituto de Salud Carlos III (PI16/, PI13/02434, PI15/00878, PI14/01126, PI11/, PI16/01861, PI14/, PI12/02288, PI08/0139, PI17/01019, PI16/01652, PI17/01895, PI11/02526)
- European Regional Development Fund (PI16/01861, PI13/02434, 01126)
- National Institute on Aging (RF1AG051504, AG046139, K23AG059891, RF AG051504, AG051504, P01AG008761, AG-005146, U19‐AG03365, NIH P50, P50AG005146, U01AG046139, R01AG061796, ZIA-NS003154, P30AG062422)
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke (NS 38377, NINDS R01 NS078086, NS078086, P50NS38377, R01NS080820, R01NS078086, NS080820, P50NS038377, U54NS100693, NS072187, P50NS072187, R35NS097261, NS100693, ZIANS003154)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- PLCγ2, non-synonymous mutations, Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, longevity, neurodegenerative diseases, genetic risk, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, etiology
- MeSH terms
- Alleles, Alzheimer Disease, Amyotrophic Lateral Sclerosis, Brain, Dementia, Humans, Longevity, Multiple Sclerosis, Mutation, Parkinson Disease, Risk, Microglia, Genetic Predisposition to Disease, Lewy Body Disease, Phospholipase C gamma, Genome-Wide Association Study, Frontotemporal Dementia, Neuroimaging
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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