PLCG2 Protective Variant p.P522R Modulates Tau Pathology and Disease Progression in Patients with Mild Cognitive Impairment

Background: A rare coding variant (rs72824905, p.P522R) conferring protection against the susceptibility to Alzheimer's disease (AD) was recently identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2). Here, we explore the protective nature of this variant with regard to AD pathology indicated by biomarkers, cognitive decline, and potential underlying biological mechanisms. Methods: Association of p.P522R with CSF levels of pTau181, total Tau and Aβ1-42 was assessed in 1,282 patients with mild cognitive impairment (MCI) or AD-dementia syndrome. In addition, the association with longitudinal cognitive decline was tested in 3,010 MCI patients from memory clinic cohorts and 10,100 individuals from population-based studies using latent process linear mixed models. Finally, unsupervised co-trans-regulatory network analysis and biological experiments were conducted. Findings: Carriers of the p.P522R variant showed lower pTau181 levels in CSF compared to non-carriers, specifically in the presence of amyloid pathology. In MCI patients but not in population-based cohorts, the p.P522R variant was associated with slower cognitive decline with an effect size similar to that of APOE-e4. We identified a network of coregulated proteins linking PLCG2 to APOE and TREM2. Finally, in vitro experiments confirmed that inflammasome activation upon phospholipase C stimulation might act downstream of PLCG2. Implication: Our data link the protective effect of p.P522R in PLCG2 to reduced Tau pathology, to a slower cognitive decline in MCI patients and to underlying inflammatory processes. Therapies targeting the enzyme PLCG2 might provide a therapeutic approach for AD. Funding Statement: EU Joint Programme Neurodegenerative Disease Research, Innovative Medicines Initiative 2, Instituto de Salud Carlos III, La Caixa, Grifols SA, German Federal Ministry of Research and Education, Sanofi Laboratories, Fondation pour la Recherche Medicale, Fondation Plan Alzheimer, Stichting Alzheimer Nederland, Stichting VUmc fonds, Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care, Netherlands Organization for Scientific Research (NWO), EMGO+ Research Institute. Declaration of Interests: All authors report no conflict of interest. PL received consultation and/or lecture honoraria from IBL International, Fujirebio Europe, AJ Roboscreen, and Roche. JW 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. LF 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 & Dohme, Novartis, Pfizer, Pharnext, Roche, Schwabe Pharma; he served on Data and Safety Monitoring boards or endpoint committees with Avraham Pharmaceuticals, Axon Neuroscience, Forschungszentrum Julich, Novartis, Pharmatropix. JP received honoraria for consulting activities, lectures or advisory board participation from Fujirebio Europe, Ono Pharma, Eli Lilly, and Nestle Institute of Health Sciences. ARu reports consulting Fees: Landsteiner Genmed, Grifols, Araclon biotech. And Lecture Fees: Araclon Biotech.PA reports personal fees from Servier, Total, Genoscreen, Takeda, Foundation Alzheimer. OP received research funding, consultancy fees or speech honoraria from Axovant, Biogen, Genentech, Lilly, Lundbeck, Novartis, Pharmatrophix, Piramal, Probiodrug, Roche, Takeda and TauRx Pharmaceuticals. MB receives fees or has received for consulting from Lab. Servier, Roche, Lilly, Avid, Bayer, Elan, Janssen, Neuroptix, Sanofi. She receives or has received fees for lectures from Lilly, Nutricia, Roche, Schwabe, Araclon, Esteve, Grifols, Janssen, Novartis, Piramal, Pfizer-Wyett, 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 & 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 Ethics Approval Statement: The individual studies were approved by the respective ethics committees.