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

Lee, Sven J. van der; Conway, Olivia J.; Jansen, Iris E.; Carrasquillo, Minerva M.; Kleineidam, Luca; Akker, Erik B. van den; Hernández, Isabel; Eijk, Kristel R. van; Stringa, Najada; Chen, Jason; Zettergren, Anna; Andlauer, Till F. M.; Díez-Fairén, Mónica; Simón‐Sánchez, 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.; Pletniková, Olga; Zulaica, Miren; Lage, Carmen; Rojas, Itziar de; Riedel‐Heller, Steffi G.; Illán‐Gala, Ignacio; Wei, Wei; Jeune, Bernard; Orellana, Adelina; Bergh, Florian Then; Wang, Xue; Hulsman, Marc; Beker, Nina; Tesi, Niccolò; Morris, Christopher M.; Indakoetxea, Begoña; Collij, Lyduine E.; Scherer, Martin; Morenas‐Rodríguez, Estrella; Ironside, James; Berckel, Bart N.M. van; Alcolea, Daniel; Wiendl, Heinz; Strickland, Samantha L.; Pástor, Pau; Rodríguez, Eloy Rodríguez; Boeve, Bradley F.; Petersen, Ronald C.; Ferman, Tanis J.; Gerpen, Jay A. van; Reinders, Marcel J. T.; Uitti, Ryan J.; Tárraga, Lluís; Maier, Wolfgang; Dols‐Icardo, Oriol; Kawalia, Amit; Dalmasso, Maria Carolina; Boada, Merçé; Zettl, Uwe K.; Schoor, Natasja M. van; Beekman, Marian; Allen, Mariet; Masliah, Eliezer; Munáin, Adolfo López de; Pantelyat, Alexander; Wszołek, Zbigniew K.; Ross, Owen A.; Dickson, Dennis W.; Graff‐Radford, Neill R.; Knopman, David S.; Rademakers, Rosa; Lemstra, Afina W.; Pijnenburg, Yolande A.L.; Scheltens, Philip; Gasser, Thomas; Chinnery, Patrick F.; Hemmer, Bernhard; Huisman, Martijn; Troncoso, Juan C.; Moreno, Fermín; Nøhr, Ellen A.; Sørensen, Thorkild I. A.; Heutink, Peter; Sánchez‐Juan, Pascual; Posthuma, Daniëlle; Clarimón, Jordi; Christensen, Kaare; Ertekin-Taner, Nilüfer; Scholz, Sonja W.; Ramı́rez, Alfredo; Ruiz, Agustín; Slagboom, Eline; Flier, Wiesje M. van der; Holstege, Henne

doi:10.1007/s00401-019-02026-8

Cited by 97 publications

(51 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This suggests that these pathways might be involved in the maintenance of general cognitive health, as the cognitively healthy centenarians represent the escape of all neurodegenerative diseases until extreme ages. We recently found evidence for this hypothesis in the protective low-frequency variant in PLCG2, which is involved in the regulation of the immune response 53 . This variant is enriched in cognitively healthy centenarians, and protects against AD, as well as frontotemporal dementia and dementia with Lewy bodies 53 .…”

Section: Discussionmentioning

confidence: 93%

“…We recently found evidence for this hypothesis in the protective low-frequency variant in PLCG2, which is involved in the regulation of the immune response 53 . This variant is enriched in cognitively healthy centenarians, and protects against AD, as well as frontotemporal dementia and dementia with Lewy bodies 53 . We included this variant in the total PRS, as well as in the pathway-PRS for the immune response (variant-pathway mapping was 60%) and endocytosis (variant-pathway mapping was 40%).…”

Section: Discussionmentioning

confidence: 93%

“…Annotation: ***p-value of association < 5 × 10 −6 ; **p-value of association < 5 × 10 −4 ; *p-value of association < 5 × 10 −2 . studies showed that PRS of AD not only associated with increased risk of AD, but also with neuropathological hallmarks of AD, lifetime risk and the age at onset in both APOE ε4 carriers and non-carriers 28,29,[51][52][53][54][55] . We now add that, using our unique cohort of cognitively healthy centenarians, the PRS for AD also associates with resilience against AD at extremely old ages.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease

et al. 2020

Self Cite

View full text Add to dashboard Cite

Developing Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N = 1895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N = 1654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N = 293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p < 0.05). The pathway that contributed most to the overall modulation of AD-risk was β-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p < 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to β-amyloid metabolism.

show abstract

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…A rare coding variant in microglia-/macrophage-specific PLCG2 gene (rs72824905, p.P522R, OR<0.6) encoding phospholipase C gamma 2 (Plcγ2) enzyme was recently identified, showing a reduced risk of AD [1]. Interestingly, the same PLCG2 variant associated with a lower risk of other neurodegenerative diseases and increased the likelihood for longevity [2]. Plcγ2 catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate (Pip2) to inositol 1,4,5-trisphosphate (Ip3) and diacylglycerol (Dag) upon activation of various transmembrane immune receptors, including Triggering receptor expressed on myeloid cells 2 (Trem2) ( Fig 1A ) [3, 4].…”

Section: Resultsmentioning

confidence: 99%

The Alzheimer’s disease-associated protectivePlcγ2-P522R variant promotes beneficial microglial functions

Takalo

Wittrahm

Wefers

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundMicroglia-specific genetic variants are enriched in several neurodegenerative diseases, including Alzheimer’s disease (AD), implicating a central role for alterations of the innate immune system in the disease etiology. A rare coding variant in the PLCG2 gene (rs72824905, p.P522R) selectively expressed in microglia and macrophages was recently identified and shown to reduce the risk for AD.MethodsTo assess the role of this variant in the context of immune cell functions, we generated a Plcγ2-P522R knock-in (KI) mouse model using CRISPR/Cas9 gene editing.ResultsFunctional analyses of macrophages derived from homozygous KI mice and wild type (WT) littermates revealed that the P522R variant potentiates the primary function of Plcγ2 as a Pip2-metabolizing enzyme. This was associated with improved survival, enhanced phagocytic activity, and increased acute inflammatory response of the KI cells. Enhanced phagocytosis was also observed in mouse BV2 microglia-like cells overexpressing human PLCγ2-P522R, but not in PLCγ2-WT expressing cells. Furthermore, the brain mRNA signature together with microglia-specific PET imaging indicated microglia activation in Plcγ2-P522R KI mice.ConclusionThus, we have delineated cellular mechanisms of the protective Plcγ2-P522R variant, which provide further support for the emerging idea that activated microglia exert protective functions in AD.

show abstract

“…In combination with the rich pool of physical, cognitive, emotional and social phenotypes in LASA, genotyping array data are a valuable resource for geneenvironment interaction studies. LASA has been included in GWAS meta-analyses from the CHARGE and GEFOS consortia recently as well as other collaborations [17][18][19].…”

Section: Genetic Datamentioning

confidence: 99%

The Longitudinal Aging Study Amsterdam: cohort update 2019 and additional data collections

et al. 2019

Self Cite

View full text Add to dashboard Cite

The Longitudinal Aging Study Amsterdam (LASA) is a prospective cohort study of older adults in the Netherlands, initially based on a nationally representative sample of people aged 55-84 years. The study has been ongoing since 1992, and focuses on the determinants, trajectories and consequences of physical, cognitive, emotional and social functioning. Strengths of the LASA study include its multidisciplinary character, the availability of over 25 years of follow-up, and the cohort-sequential design that allows investigations of longitudinal changes, cohort differences and time trends in functioning. The findings from LASA have been reported in over 600 publications so far (see www.lasa-vu.nl). This article provides an update of the design of the LASA study and its methods, on the basis of recent developments. We describe additional data collections, such as additional nine-monthly measurements in-between the regular three-yearly waves that have been conducted among the oldest old during 2016-2019, and the inclusion of a cohort of older Turkish and Moroccan migrants.

show abstract

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

Cited by 97 publications

References 58 publications

Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease

Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease

The Alzheimer’s disease-associated protectivePlcγ2-P522R variant promotes beneficial microglial functions

The Longitudinal Aging Study Amsterdam: cohort update 2019 and additional data collections

Contact Info

Product

Resources

About