[en] Increasing evidence points to a pivotal role of immune processes in the pathogenesis of Alzheimer disease, which is the most prevalent neurodegenerative and dementia-causing disease of our time. Multiple lines of information provided by experimental, epidemiological, neuropathological and genetic studies suggest a pathological role for innate and adaptive immune activation in this disease. Here, we review the cell types and pathological mechanisms involved in disease development as well as the influence of genetics and lifestyle factors. Given the decade-long preclinical stage of Alzheimer disease, these mechanisms and their interactions are driving forces behind the spread and progression of the disease. The identification of treatment opportunities will require a precise understanding of the cells and mechanisms involved as well as a clear definition of their temporal and topographical nature. We will also discuss new therapeutic strategies for targeting neuroinflammation, which are now entering the clinic and showing promise for patients.
Disciplines :
Neurology
Author, co-author :
HENEKA, Michael ; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette/Belvaux, Luxembourg
van der Flier, Wiesje M; Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands
Jessen, Frank; Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany
Hoozemanns, Jeroen; Department of Pathology, Amsterdam Neuroscience, Amsterdam University Medical Centre, Amsterdam, The Netherlands
Thal, Dietmar Rudolf ; Department of Pathology, University Hospitals Leuven, Leuven, Belgium ; Laboratory for Neuropathology, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium ; Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), Leuven, Belgium
Boche, Delphine ; Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
Brosseron, Frederic ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Teunissen, Charlotte ; Department of Laboratory Medicine, VUMC Amsterdam, Amsterdam, The Netherlands
Zetterberg, Henrik; Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden
Jacobs, Andreas H; European Institute for Molecular Imaging, University of Münster, Münster, Germany
Edison, Paul ; Division of Neurology, Department of Brain Sciences, Imperial College London, London, UK
Ramirez, Alfredo ; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany ; Cluster of Excellence Cellular Stress Response in Aging-associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Cruchaga, Carlos; Department of Psychiatry, Washington School of Medicine in St. Louis, St. Louis, MO, USA
Lambert, Jean-Charles ; Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France
Laza, Agustin Ruiz ; ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), Barcelona, Spain
Sanchez-Mut, Jose Vicente ; Instituto de Neurociencias, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas (UMH-CSIC), Alicante, Spain
Fischer, Andre ; Clinic for Psychiatry and Psychotherapy, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany ; Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Centre for Neurodegenerative Disease (DZNE), Göttingen, Germany
Castro-Gomez, Sergio ; Center for Neurology, Clinic of Parkinson, Sleep and Movement Disorders, University Hospital Bonn, University of Bonn, Bonn, Germany ; Institute of Physiology II, University Hospital Bonn, University of Bonn, Bonn, Germany ; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, Bonn, Germany
Stein, Thor D; Boston University Alzheimer's Disease Research Center and CTE Center, Department of Pathology & Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
Kleineidam, Luca ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University Hospital Bonn, University of Bonn, Bonn, Germany
Wagner, Michael ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University Hospital Bonn, University of Bonn, Bonn, Germany
Neher, Jonas J; Biomedical Center Munich, Biochemistry, Medical Faculty, LMU Munich, Munich, Germany ; Neuroimmunology and Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
Cunningham, Colm; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, Dublin, Ireland ; Trinity College Institute of Neuroscience (TCIN), Trinity College Dublin, Dublin, Ireland
Singhrao, Sim K; Brain and Behaviour Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK
Prinz, Marco ; Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany ; Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
Glass, Christopher K; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA ; Department of Medicine, University of California San Diego, La Jolla, CA, USA
Schlachetzki, Johannes C M; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA ; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
Butovsky, Oleg; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Kleemann, Kilian; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
De Jaeger, Philip L ; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA ; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
Scheiblich, Hannah; Center for Neurology, Clinic of Parkinson, Sleep and Movement Disorders, University Hospital Bonn, University of Bonn, Bonn, Germany
Brown, Guy C ; Deparment of Biochemistry, University of Cambridge, Cambridge, UK
Landreth, Gary ; School of Medicine, Indiana University, Indianapolis, IN, USA
Moutinho, Miguel ; School of Medicine, Indiana University, Indianapolis, IN, USA
Grutzendler, Jaime ; Department of Neurology, Yale School of Medicine, New Haven, CT, USA ; Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA
Gomez-Nicola, Diego ; School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
McManus, Róisín M ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Andreasson, Katrin ; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
Ising, Christina ; Cluster of Excellence Cellular Stress Response in Aging-associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany ; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Karabag, Deniz; Cluster of Excellence Cellular Stress Response in Aging-associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Baker, Darren J; Department of Paediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA ; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
Liddelow, Shane A ; Neuroscience Institute, NYU Grossman School of Medicine, New York City, NY, USA ; Department of Neuroscience and Physiology, NYU Grossman School of Medicine, New York City, NY, USA ; Department of Ophthalmology, NYU Grossman School of Medicine, New York City, NY, USA
Verkhratsky, Alexei ; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
Tansey, Malu ; College of Medicine, University of Florida, Gainsville, FL, USA
Monsonego, Alon ; Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Aigner, Ludwig ; Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria
Dorothée, Guillaume ; Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Hôpital Saint-Antoine, Paris, France
Nave, Klaus-Armin ; Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
Simons, Mikael; Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
Constantin, Gabriela ; Section of General Pathology, Department of Medicine, University of Verona, Verona, Italy
Rosenzweig, Neta; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Pascual, Alberto ; Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
Petzold, Gabor C ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Vascular Neurology, University of Bonn, Bonn, Germany
Kipnis, Jonathan ; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA ; Center for Brain Immunology and Glia (BIG), Washington University School of Medicine, St. Louis, MO, USA
VENEGAS MALDONADO, Carmen Jesica ; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette/Belvaux, Luxembourg ; Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain ; Instituto Biosanitario de Granada (ibs.Granada), Granada, Spain
Colonna, Marco ; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
Walter, Jochen ; Center of Neurology, University Hospital Bonn, University of Bonn, Bonn, Germany
Tenner, Andrea J ; Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, CA, USA ; Department of Neurobiology and Behaviour, University of California Irvine, Irvine, CA, USA ; Department of Pathology and Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA, USA
O'Banion, M Kerry ; Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA ; Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA
Steinert, Joern R; Faculty of Medicine and Health Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK
Feinstein, Douglas L; Department of NeuroAnesthesia, University of Illinois at Chicago, Chicago, IL, USA
Sastre, Magdalena ; Department of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK
Bhaskar, Kiran ; Department of Molecular Genetics & Microbiology and Neurology, University of New Mexico, Albuquerque, NM, USA
Hong, Soyon ; UK Dementia Research Institute, Institute of Neurology, University College London, London, UK
Schafer, Dorothy P; Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
Golde, Todd; Department of Pharmacology and Chemical Biology, Emory Center for Neurodegenerative Disease, Emory University, Atlanta, GA, USA ; Department of Neurology, Emory Center for Neurodegenerative Disease, Emory University, Atlanta, GA, USA
Ransohoff, Richard M ; Third Rock Ventures, Boston, MA, USA
Morgan, David ; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
Breitner, John; Department of Psychiatry, McGill University Faculty of Medicine, Montreal, Québec, Canada
Mancuso, Renzo ; Microglia and Inflammation in Neurological Disorders (MIND) Lab, VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium ; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
RIECHERS, Sean-Patrick Hermann ; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette/Belvaux, Luxembourg
A.F. received funds from Germany\u2019s Excellence Strategy (EXC 2067/1 390729940). A.J.T. is supported by the National Institutes of Health (NIH) grant (U54 AG054349). D.L.F. is supported by grant IK6BX004852-01 from the Department of Veterans Affairs. D.B. acknowledges support from the Medical Research Council UK, Alzheimer\u2019s Research UK and the European Union. She thanks the UK Brain Banks and BRAIN UK for providing tissue for her studies. D.J.B. is supported by the NIH (R01AG053229, R01AG068076, U54AG079779), the Minnesota Partnership for Biotechnology and Medical Genomics (MNP #18.04), and the Glenn Foundation for Medical Research. C.Cunningham is funded by the Irish Research Council, National Institutes of Health, the Dutch Research Council (ZonMW) and Alzheimer\u2019s Research UK. D.G.-N. was supported by grants from the Medical Research Council (MR/P024572/1, MR/Y004116/1). C.V. was supported by the RYC2022-036191-I, funded by MCIN/AEI/10.13039/501100011033 and European Social Fund Plus. C.T. is supported by the European Commission Marie Curie International Training Network, grant agreement No. 860197 (MIRIADE) and TAME, Innovative Medicines Initiatives 3TR (Horizon 2020, grant No. 831434), EPND (IMI 2 Joint Undertaking (JU), grant No. 101034344) and JPND (bPRIDE, CCAD), European Partnership on Metrology, co-financed from the European Union\u2019s Horizon Europe Research and Innovation Programme and by the Participating States (22HLT07 NEuroBioStand), CANTATE project funded by the Alzheimer Drug Discovery Foundation, Alzheimer Association, Michael J Fox Foundation, Health Holland, ZonMW, Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, and Alzheimer Netherlands. C.T. is a recipient of ABOARD, which is a public\u2013private partnership receiving funding from ZonMW (#73305095007) and Health Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). C.T. is a recipient of TAP-dementia, a ZonMw-funded project (#10510032120003) in the context of the Dutch National Dementia Strategy. D.M. is supported by ZEN24-1070221 from the Alzheimer\u2019s Association and R01 AG055072, R01 AG077651, and P30 AG072931 from NIH. D.R.T. received support from Research Foundation \u2013 Flanders (FWO; G065721N), Stichting Alzheimer Onderzoek (SAO/FRA 2023/0009) and Alzheimer\u2019s Association (22-AAIIA-963171). D.S. was supported by NINDS-R01NS117533, NIA-RF1AG068281 and NIH-R24OD036199. G.C. is supported by the NextGenerationEU and National Recovery and Resilience Plan, National Biodiversity Future Center and PE grant MNESYS (PE0000006). G.C.P. received funding from the German Science Foundation (PE1193/6-2), ERA-NET (MICRO-BLEEDs and TACKLE-CSVD), and the Fondation Leducq (Transatlantic Network of Excellence 23CVD03); he is a member of the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) excellence cluster ImmunoSensation2. G.D. thanks the Agence Nationale de la Recherche (grants #ANR-21-CE17-0054-01; #ANR-24-CE18-2770-02), Fondation Alzheimer, Fondation pour la Recherche M\u00E9dicale, Fondation Pierre Deniker, Association France Alzheimer and Fondation Vaincre Alzheimer for funding his research. H.Z. is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023-00356; #2022-01018 and #2019-02397), the European Union\u2019s Horizon Europe Research and Innovation Programme under grant agreement No. 101053962, and Swedish State Support for Clinical Research (#ALFGBG-71320). J.B. was supported by a research grant from the Canada Institute for Health Research. J.G. was funded by the JPB Foundation, the Cure Alzheimers Fund and The Alzheimer\u2019s Association. J.C.M.S. is supported by a clinical fellowship from the Alzheimer\u2019s Association (AACSF). J.V.S.-M. is supported by grants from the Pasqual Maragall Foundation (PMRP/2022/1184) and Spanish (PID2022-143263OB-I00) and Valencian (PROMETEO/2021/045) governments. K.-A.N. has been supported by grants from the DFG (TRR274), European Research Council (ERC; AdG MyeliNANO) and the Adelson Medical Research Foundation (AMRF). K.B. was funded by the NIH grant RF1NS083704. L.A. is supppoted by the Austrian Science Fund FWF Project #P35417-B. K.A. is the Edward F. and Irene Thiele Pimley Professor of Neurology and Neurological Sciences and is supported by NIH grants RF1 AG070839, RF1 AG079131, and RF1 AG080742, the Wu Tsai Neurosciences Institute Knight Initiative for Brain Resilience at Stanford University, and she is a Chan Zuckerberg Biohub-San Francisco Investigator. M.K.O. is supported by grant 80NSSC21K0542 from NASA. O.B. is funded by grants from NIH-STTR (R41AG073059), Cure Alzheimer Fund, BrightFocus Foundation (2020A016806), NIH/NIA (R01 AG051812), NIH (R01 AG054672), NIH (R01 AG075509), NIH (R01 NS088137-10), NIH (R21AG076982), and NIH/NINDS (R01 NS088137). R.Mancuso has funding from the ERC under the European Union\u2019s Horizon 2020 Research and Innovation Programme (project no. 101041867 - XenoMicrogliaAD), Fonds voor Wetenschappelijk Onderzoek (grants No. G0C9219N, G056022N and G0K9422N), the Alzheimer\u2019s Association USA (2018-AARF-591110, 2018-AARF-591110-RAPID, E2A-23-1148152, ABA-22-968700). He also receives funding from BrightFocus Foundation (A2021034S), SAO-FRA (grants No. 2021/0021 and SAO-FRA 20230019) and the University of Antwerp (BOF-TOP 2022-2025). R.McManus is supported by grants from the European Union Joint Programme Neurodegenerative Disease (JPND) (01ED2409B), the Alzheimer\u2019s Association (24AARF-1243474) and from the DFG, under Germany\u2019s Excellence Strategy \u2013 EXC2151 \u2013 390873048, along with Project-ID 432325352 \u2013 SFB 1454. S.C.G. is supported by the Alzheimer Forschung Initiative e.V (Grant 21060), the Hertie Network of Excellence in Clinical Neuroscience (Grant 2021-1A-12), the Bonn Neuroscience Clinician Scientist Program (Neuro-aCSis), and the DFG (EXC2151\u2013390873048). S.H. is supported by the UK Dementia Research Institute (UKDRI-1011) and the Chan Zuckerberg Initiative Neurodegeneration Network. J.J.N. is currently supported through Germany\u2019s Excellence Strategy (EXC 2145 SyNergy\u2013 ID 390857198), the Else Kr\u00F6ner-Fresenius Stiftung (2018-A158), the Charitable Hertie Foundation (P1200024), the BrightFocus Foundation (A2021035S) and Alzheimer\u2019s Association (ADSF-24-1345513-C). W.M.vdF. performs research at the Alzheimer Center Amsterdam as part of the neurodegeneration research programme of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting Steun Alzheimercentrum Amsterdam. The chair held by W.M.vdF. is supported by the Pasman Stichting. W.M.vdF. is a recipient of ABOARD, which is a public\u2013private partnership receiving funding from ZonMW (#73305095007) and Health Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). W.M.vdF. is a recipient of TAP-dementia ( www.tap-dementia.nl ), receiving funding from ZonMw (#10510032120003).
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