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Cited by 62Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

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Alzheimer’s Disease Neuroimaging Initiative (ADNI), Kleineidam, Luca, Chouraki, Vincent, Próchnicki, Tomasz, van der Lee, Sven J., Madrid-Márquez, Laura, Wagner-Thelen, Holger, Karaca, Ilker +48 more·2020·Acta Neuropathologica
DOI 10.1007/s00401-020-02138-6PMC PMC7244617
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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.

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  • PLCG2 polymorphisms are associated with both reduced and increased risk of Alzheimer's disease and with longevity.

    “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 [4]

    The Introduction (page not available) says the PLCG2 p.P522R variant protects against Alzheimer’s disease and reports a suggested positive effect on longevity. Neither that passage nor the retrieved passages identify a PLCG2 variant associated with increased Alzheimer’s risk, so that part of the claim is unsupported by our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • PLCG2 expression is associated with both amyloid and tau pathology.

    “PLCG2 expression has also been associated with both amyloid and tau pathology (4, 11).”

    From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [4]

    The Discussion (page unavailable) links the PLCG2 p.P522R variant to reduced tau pathology in patients with mild cognitive impairment, with its strongest effect when amyloid pathology is present. That supports a connection to both pathologies, but the paper does not establish that PLCG2 expression itself is associated with both; it studies variant status and a separate co-expression network. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The P522R mutation in PLCG2 protects against Alzheimer's disease-related cognitive decline.

    “Genome-wide association studies have identified a protective mutation in the phospholipase C gamma 2 (PLCG2) gene which confers protection against Alzheimer’s disease (AD)-associated cognitive decline.”

    From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [7]

    The Abstract and Discussion report that PLCG2 p.P522R carriers with mild cognitive impairment had slower cognitive decline, particularly when amyloid pathology was present. The citing sentence omits that population qualifier: the Abstract also reports no protective effect on cognitive decline in the population-based studies. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The mildly hypermorphic PLCG2P522R variant is associated with increased longevity, improved clearance of Aβ, and protection against AD.

    “With respect to AD, the mildly hypermorphic PLCG2P522R variant is associated with increased longevity, improved clearance of Aβ, and protection against AD.”

    From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [24]

    The Introduction reports that p.P522R slightly increases PLCG2 activity, is associated with protection against AD, and has been suggested to have a positive effect on longevity. The Discussion and Results do not support improved Aβ clearance: they report no association with Aβ1-42 pathology and place the observed protective effect downstream of amyloid accumulation, chiefly through reduced tau pathology. Page numbers are not available in our copy. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

  • Individuals with MCI who carry the PLCγ2P522R variant had better cognitive performance even in the presence of the APOE4 AD risk gene.

    “It has recently been reported that individuals with MCI (mild cognitive impairment), who carry the PLCγ2P522R variant had better cognitive performance even in the presence of the APOE4 AD risk gene [38].”

    From Heterozygous expression of the Alzheimer’s disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses (2022) · cites this paper as [38]

    The Results section reports slower cognitive decline among MCI patients carrying p.P522R and compares its effect in the presence of APOE-ε4. But it says the variant *may* initially counteract APOE-ε4’s detrimental effect, at least in part; the claim presents better cognitive performance in those carrying both variants as a definite finding. No page number was provided for the indexed passage. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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References 92 · Cited by 62

Research works printed but not linked: 54

  1. [1]Abdelnour C van Steenoven I Londos E Alzheimer’s disease cerebrospinal fluid biomarkers predict cognitive decline in lewy body dementia Mov Disord 2016 31 8 1203 1208 27296778
  2. [2]Abner EL Kryscio RJ Schmitt FA Outcomes after diagnosis of mild cognitive impairment in a large autopsy series Ann Neurol 2017 81 4 549 559 28224671 PMC5401633
  3. [4]Asai H Ikezu S Tsunoda S Depletion of microglia and inhibition of exosome synthesis halt tau propagation Nat Neurosci 2015 18 11 1584 1593 26436904 PMC4694577
  4. [7]Braak H Thal DR Ghebremedhin E Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years J Neuropathol Exp Neurol 2011 70 11 960 969 22002422
  5. [9]Cohen G Makranz C Spira M Non-PKC DAG/Phorbol-Ester receptor (s) inhibit complement receptor-3 and nPKC inhibit scavenger receptor-AI/II-mediated myelin phagocytosis but cPKC, PI3k, and PLCγ activate myelin phagocytosis by both Glia 2006 53 5 538 550 16374778
  6. [12]Dagher NN Najafi AR Kayala KMN Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice J Neuroinflamm 2015 12 1 139 PMC4522109 26232154
  7. [15]Enders CK Applied missing data analysis 2010 New York Guilford Press
  8. [16]Ferrari R Wang Y Vandrovcova J Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer’s and Parkinson’s diseases J Neurol Neurosurg Psychiatry 2017 88 2 152 164 27899424 PMC5237405
  9. [17]Finan C Gaulton A Kruger FA The druggable genome and support for target identification and validation in drug development Sci Transl Med 2017 9 383 eaag1166 28356508 PMC6321762
  10. [18]Fjell AM McEvoy L Holland D What is normal in normal aging? Effects of aging, amyloid and Alzheimer’s disease on the cerebral cortex and the hippocampus Prog Neurobiol 2014 117 20 40 24548606 PMC4343307
  11. [21]Hammond TR Marsh SE Stevens B Immune signaling in neurodegeneration Immunity 2019 50 4 955 974 30995509 PMC6822103
  12. [23]Hayat SA Luben R Dalzell N Understanding the relationship between cognition and death: a within cohort examination of cognitive measures and mortality Eur J Epidemiol 2018 33 11 1049 1062 30203336 PMC6208995
  13. [24]Heckman MG Kasanuki K Brennan RR Association of MAPT H1 subhaplotypes with neuropathology of lewy body disease Mov Disord 2019 34 1325 1332 31234228 PMC7996001
  14. [25]Herrup K Reimagining Alzheimer’s disease—an age-based hypothesis J Neurosci 2010 30 50 16755 16762 21159946 PMC3004746
  15. [26]Hohman TJ Tommet D Marks S Evaluating Alzheimer’s disease biomarkers as mediators of age-related cognitive decline Neurobiol Aging 2017 58 120 128 28732249 PMC5710827
  16. [30]Jack CR Jr Clifford R Knopman DS Jagust WJ Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers Lancet Neurol 2013 12 2 207 216 23332364 PMC3622225
  17. [31]Jagust W Vulnerable neural systems and the borderland of brain aging and neurodegeneration Neuron 2013 77 2 219 234 23352159 PMC3558930
  18. [32]Jansen WJ Ossenkoppele R Knol DL Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis Jama 2015 313 19 1924 1938 25988462 PMC4486209
  19. [33]Jansen IE Savage JE Watanabe K Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk Nat Genet 2019 51 404 413 30617256 PMC6836675
  20. [34]Jay TR von Saucken VE Landreth GE TREM2 in neurodegenerative diseases Mol Neurodegener 2017 12 1 56 28768545 PMC5541421
  21. [35]Jones L Lambert J-C Wang L-S Convergent genetic and expression data implicate immunity in Alzheimer’s disease Alzheimers Dement 2015 11 6 658 671 25533204 PMC4672734
  22. [36]Jun G Ibrahim-Verbaas CA Vronskaya M A novel Alzheimer disease locus located near the gene encoding tau protein Mol Psychiatry 2016 21 1 108 25778476 PMC4573764
  23. [37]Kamb A Harper S Stefansson K Human genetics as a foundation for innovative drug development Nat Biotechnol 2013 31 11 975 24213769
  24. [39]Keren-Shaul H Spinrad A Weiner A A unique microglia type associated with restricting development of Alzheimer’s disease Cell 2017 169 7 1276 1290 28602351
  25. [41]Kunkle BW Grenier-Boley B Sims R Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing Nat Genet 2019 51 3 414 430 30820047 PMC6463297
  26. [44]Lee CD Daggett A Gu X Elevated TREM2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in Alzheimer’s disease models Neuron 2018 97 5 1032 1048 29518357 PMC5927822
  27. [45]Liao Y Wang J Jaehnig EJ WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs Nucleic Acids Res 2019 47 W1 W100 W205 PMC6602449 31114916
  28. [46]Lill CM Rengmark A Pihlstrøm L The role of TREM2 R47H as a risk factor for Alzheimer’s disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson’s disease Alzheimers Dement 2015 11 12 1407 1416 25936935 PMC4627856
  29. [48]Makranz C Cohen G Baron A Phosphatidylinositol 3-kinase, phosphoinositide-specific phospholipase-Cγ and protein kinase-C signal myelin phagocytosis mediated by complement receptor-3 alone and combined with scavenger receptor-AI/II in macrophages Neurobiol Dis 2004 15 2 279 286 15006698
  30. [49]Mathys H Davila-Velderrain J Peng Z Single-cell transcriptomic analysis of Alzheimer’s disease Nature 2019 570 7761 332 337 31042697 PMC6865822
  31. [52]Ombrello MJ Remmers EF Sun G Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions N Engl J Med 2012 366 4 330 338 22236196 PMC3298368
  32. [53]Ossenkoppele R Jansen WJ Rabinovici GD Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis Jama 2015 313 19 1939 1950 25988463 PMC4517678
  33. [54]Peng Q Malhotra S Torchia JA TREM2-and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1 Sci Signal 2010 3 122 ra38 ra38 20484116 PMC2900152
  34. [55]Plenge RM Scolnick EM Altshuler D Validating therapeutic targets through human genetics Nat Rev Drug Discov 2013 12 8 581 23868113
  35. [56]Proust-Lima C Dartigues J-F Jacqmin-Gadda H Misuse of the linear mixed model when evaluating risk factors of cognitive decline Am J Epidemiol 2011 174 9 1077 1088 21965187 PMC3551607
  36. [57]Proust-Lima C Philipps V Liquet B Estimation of extended mixed models using latent classes and latent processes: The R package lcmm J Stat Softw 2017 78 2 56 10.18637/jss.v078.i02 · DOI
  37. [60]Rauchmann B-S Schneider-Axmann T Alexopoulos P CSF soluble TREM2 as a measure of immune response along the Alzheimer’s disease continuum Neurobiol Aging 2019 74 182 190 30458365 PMC6331262
  38. [62]Roberts R Knopman DS Classification and epidemiology of MCI Clin Geriatr Med 2013 29 4 753 772 24094295 PMC3821397
  39. [63]Roberts RO Aakre JA Kremers WK Prevalence and outcomes of amyloid positivity among persons without dementia in a longitudinal, population-based setting JAMA Neurol 2018 75 8 970 979 29710225 PMC6142936
  40. [64]Rongve A Witoelar A Ruiz A GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study Sci Rep 2019 9 1 7013 31065058 PMC6504850
  41. [65]Schulze-Luehrmann J Ghosh S Antigen-receptor signaling to nuclear factor κB Immunity 2006 25 5 701 715 17098202
  42. [66]Shen M-Y Hsiao G Fong T-H Expression of amyloid beta peptide in human platelets: pivotal role of the phospholipase Cγ2-protein kinase C pathway in platelet activation Pharmacol Res 2008 57 2 151 158 18313326
  43. [67]Shi Y Holtzman DM Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight Nat Rev Immunol 2018 18 12 759 772 30140051 PMC6425488
  44. [69]Song WM Joshita S Zhou Y Humanized TREM2 mice reveal microglia-intrinsic and-extrinsic effects of R47H polymorphism J Exp Med 2018 215 3 745 760 29321225 PMC5839761
  45. [73]Stancu I-C Cremers N Vanrusselt H Aggregated Tau activates NLRP3–ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo Acta Neuropathol 2019 137 4 599 617 30721409 PMC6426830
  46. [75]Szklarczyk D Gable AL Lyon D STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets Nucleic Acids Res 2018 47 D1 D607 D613 PMC6323986 30476243
  47. [76]Terry RD Masliah E Salmon DP Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment Ann Neurol 1991 30 4 572 580 1789684
  48. [77]van Dam S Cordeiro R Craig T GeneFriends: an online co-expression analysis tool to identify novel gene targets for aging and complex diseases BMC Genom 2012 13 1 535 PMC3495651 23039964
  49. [79]Venegas C Kumar S Franklin BS Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease Nature 2017 552 7685 355 361 29293211
  50. [80]Waegaert R Dirrig-Grosch S Parisot F Longitudinal transcriptomic analysis of altered pathways in a CHMP2Bintron5-based model of ALS-FTD Neurobiol Dis 2020 136 104710 31837425
  51. [84]Yeh FL Wang Y Tom I TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia Neuron 2016 91 2 328 340 27477018
  52. [86]Zanoni I Ostuni R Marek LR CD14 controls the LPS-induced endocytosis of Toll-like receptor 4 Cell 2011 147 4 868 880 22078883 PMC3217211
  53. [88]Zhang B Gaiteri C Bodea L-G Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease Cell 2013 153 3 707 720 23622250 PMC3677161
  54. [89]Zhou HH Singh V Johnson SC Statistical tests and identifiability conditions for pooling and analyzing multisite datasets Proc Natl Acad Sci 2018 115 7 1481 1486 29386387 PMC5816202

Authors
(ADNI), A. D. N. I., Kleineidam, L., Chouraki, V., Próchnicki, T., van der Lee, S. J., Madrid-Márquez, L., Wagner-Thelen, H., Karaca, I., Weinhold, L., Wolfsgruber, S., Boland, A., Martino Adami, P. V., Lewczuk, P., Popp, J., Brosseron, F., Jansen, I. E., Hulsman, M., Kornhuber, J., Peters, O., Berr, C., Heun, R., Frölich, L., Tzourio, C., Dartigues, J.-F., Hüll, M., Espinosa, A., Hernández, I., de Rojas, I., Orellana, A., Valero, S., Stringa, N., van Schoor, N. M., Huisman, M., Scheltens, P., Rüther, E., Deleuze, J.-F., Wiltfang, J., Tarraga, L., Schmid, M., Scherer, M., Riedel-Heller, S., Heneka, M. T., Amouyel, P., Jessen, F., Boada, M., Maier, W., Schneider, A., González-Pérez, A., van der Flier, W. M., Wagner, M., Lambert, J.-C., Holstege, H., Sáez, M. E., Latz, E., Ruiz, A., & Ramirez, A.
Affiliations
  • University of Cologne (DE)
  • Inserm (FR)
  • University Hospital Bonn (DE)
  • Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
  • Medical University of Białystok (PL)
  • Centre Hospitalier Universitaire Vaudois (CH)
  • Amsterdam Neuroscience (NL)
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • German Center for Neurodegenerative Diseases (DE)
  • Heidelberg University (DE)
  • Université de Bordeaux (FR)
  • University of Freiburg (DE)
  • Instituto de Salud Carlos III (ES)
  • Universitat Internacional de Catalunya (ES)
  • Amsterdam Public Health (NL)
  • Universitätsmedizin Göttingen (DE)
  • University Medical Center Hamburg-Eppendorf (DE)
  • Leipzig University (DE)
  • University of Massachusetts Chan Medical School (US)
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2020-03-12
Volume
139
Issue
6
Pages
1025-1044
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-020-02138-6
PMC
PMC7244617
OpenAlex
W3011167359
Cited by
62
References
92
Citations by year
2026: 4 · 2025: 8 · 2024: 10 · 2023: 8 · 2022: 12 · 2021: 11 · 2020: 8 · 2018: 1
FWCI
3.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion, cc-by)
  • SSRN Electronic Journal (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • VU Research Portal (publishedVersion, other-oa)
  • SERVAL (Université de Lausanne) (publishedVersion, cc-by)
  • HAL (submittedVersion, cc-by)
  • IRIS (submittedVersion, cc-by)
  • Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
  • OPUS Repository (Kooperativer Bibliotheksverbund Berlin-Brandenburg) (submittedVersion, cc-by)
  • The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
  • Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion, cc-by)
  • DZNE Pub (submittedVersion, cc-by)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • Bundesministerium für Bildung und Forschung (01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434, 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, 01ET1006B, 01EA1410A, 01ED1619A)
  • Deutsche Forschungsgemeinschaft (RA 1971/6-1)
  • ZonMw (733051061)
  • Innovative Medicines Initiative (115975, 115372)
  • Instituto de Salud Carlos III (PI13/02434, PI16/01861, PI19/01301)
  • Netherlands Organization for Scientific Research (480-10-014)
  • Swiss National Science Foundation (320030L_141179)
Topics
  • Health Sciences › Medicine › Physiology › 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, Alzheimer's disease, mild cognitive impairment, tau pathology, phosphorylated tau, cognitive decline, amyloid-beta, APOE ε4, TREM2, microglia, complement system, disease progression, protective genetic variants, therapeutic target
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Cognition, Female, Humans, Male, Middle Aged, Biomarkers, Amyloid beta-Peptides, tau Proteins, Disease Progression, Phospholipase C gamma, Cognitive Dysfunction

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