Neuroinflammation in Alzheimer disease

  • Nat Rev Immunol. 2025 May;25(5):321-352. doi: 10.1038/s41577-024-01104-7.
Michael T Heneka  1 ,  Wiesje M van der Flier  2 ,  Frank Jessen  3 ,  Jeroen Hoozemanns  4 ,  Dietmar Rudolf Thal  5  6  7 ,  Delphine Boche  8 ,  Frederic Brosseron  9 ,  Charlotte Teunissen  10 ,  Henrik Zetterberg  11 ,  Andreas H Jacobs  12 ,  Paul Edison  13 ,  Alfredo Ramirez  14  15 ,  Carlos Cruchaga  16 ,  Jean-Charles Lambert  17 ,  Agustin Ruiz Laza  18 ,  Jose Vicente Sanchez-Mut  19 ,  Andre Fischer  20  21 ,  Sergio Castro-Gomez  22  23  24 ,  Thor D Stein  25 ,  Luca Kleineidam  9  26 ,  Michael Wagner  26 ,  Jonas J Neher  27  28 ,  Colm Cunningham  29  30 ,  Sim K Singhrao  31 ,  Marco Prinz  32  33 ,  Christopher K Glass  34  35 ,  Johannes C M Schlachetzki  34  36 ,  Oleg Butovsky  37 ,  Kilian Kleemann  37 ,  Philip L De Jaeger  38  39 ,  Hannah Scheiblich  22 ,  Guy C Brown  40 ,  Gary Landreth  41 ,  Miguel Moutinho  41 ,  Jaime Grutzendler  42  43 ,  Diego Gomez-Nicola  44 ,  Róisín M McManus  9 ,  Katrin Andreasson  45 ,  Christina Ising  15  46 ,  Deniz Karabag  15 ,  Darren J Baker  47  48 ,  Shane A Liddelow  49  50  51 ,  Alexei Verkhratsky  52 ,  Malu Tansey  53 ,  Alon Monsonego  54 ,  Ludwig Aigner  55 ,  Guillaume Dorothée  56 ,  Klaus-Armin Nave  57 ,  Mikael Simons  58 ,  Gabriela Constantin  59 ,  Neta Rosenzweig  37 ,  Alberto Pascual  60 ,  Gabor C Petzold  9  61 ,  Jonathan Kipnis  62  63 ,  Carmen Venegas  64  65  66 ,  Marco Colonna  62 ,  Jochen Walter  67 ,  Andrea J Tenner  68  69  70 ,  M Kerry O'Banion  71  72 ,  Joern R Steinert  73 ,  Douglas L Feinstein  74 ,  Magdalena Sastre  75 ,  Kiran Bhaskar  76 ,  Soyon Hong  77 ,  Dorothy P Schafer  78 ,  Todd Golde  79  80 ,  Richard M Ransohoff  81 ,  David Morgan  82 ,  John Breitner  83 ,  Renzo Mancuso  84  85 ,  Sean-Patrick Riechers  64
Affiliations
  • 1. Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette/Belvaux, Luxembourg. [email protected].
  • 2. Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands.
  • 3. Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.
  • 4. Department of Pathology, Amsterdam Neuroscience, Amsterdam University Medical Centre, Amsterdam, The Netherlands.
  • 5. Department of Pathology, University Hospitals Leuven, Leuven, Belgium.
  • 6. Laboratory for Neuropathology, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
  • 7. Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), Leuven, Belgium.
  • 8. Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
  • 9. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
  • 10. Department of Laboratory Medicine, VUMC Amsterdam, Amsterdam, The Netherlands.
  • 11. Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.
  • 12. European Institute for Molecular Imaging, University of Münster, Münster, Germany.
  • 13. Division of Neurology, Department of Brain Sciences, Imperial College London, London, UK.
  • 14. Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.
  • 15. Cluster of Excellence Cellular Stress Response in Aging-associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • 16. Department of Psychiatry, Washington School of Medicine in St. Louis, St. Louis, MO, USA.
  • 17. Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France.
  • 18. ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), Barcelona, Spain.
  • 19. Instituto de Neurociencias, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas (UMH-CSIC), Alicante, Spain.
  • 20. Clinic for Psychiatry and Psychotherapy, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.
  • 21. Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Centre for Neurodegenerative Disease (DZNE), Göttingen, Germany.
  • 22. Center for Neurology, Clinic of Parkinson, Sleep and Movement Disorders, University Hospital Bonn, University of Bonn, Bonn, Germany.
  • 23. Institute of Physiology II, University Hospital Bonn, University of Bonn, Bonn, Germany.
  • 24. Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, Bonn, Germany.
  • 25. 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.
  • 26. Department of Neurodegenerative Disease and Geriatric Psychiatry, University Hospital Bonn, University of Bonn, Bonn, Germany.
  • 27. Biomedical Center Munich, Biochemistry, Medical Faculty, LMU Munich, Munich, Germany.
  • 28. Neuroimmunology and Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
  • 29. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, Dublin, Ireland.
  • 30. Trinity College Institute of Neuroscience (TCIN), Trinity College Dublin, Dublin, Ireland.
  • 31. Brain and Behaviour Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK.
  • 32. Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany.
  • 33. Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.
  • 34. Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • 35. Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  • 36. Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • 37. Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 38. Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
  • 39. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA.
  • 40. Deparment of Biochemistry, University of Cambridge, Cambridge, UK.
  • 41. School of Medicine, Indiana University, Indianapolis, IN, USA.
  • 42. Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
  • 43. Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA.
  • 44. School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK.
  • 45. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • 46. Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • 47. Department of Paediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
  • 48. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
  • 49. Neuroscience Institute, NYU Grossman School of Medicine, New York City, NY, USA.
  • 50. Department of Neuroscience and Physiology, NYU Grossman School of Medicine, New York City, NY, USA.
  • 51. Department of Ophthalmology, NYU Grossman School of Medicine, New York City, NY, USA.
  • 52. Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
  • 53. College of Medicine, University of Florida, Gainsville, FL, USA.
  • 54. Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
  • 55. Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria.
  • 56. Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Hôpital Saint-Antoine, Paris, France.
  • 57. Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • 58. Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany.
  • 59. Section of General Pathology, Department of Medicine, University of Verona, Verona, Italy.
  • 60. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
  • 61. Department of Vascular Neurology, University of Bonn, Bonn, Germany.
  • 62. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
  • 63. Center for Brain Immunology and Glia (BIG), Washington University School of Medicine, St. Louis, MO, USA.
  • 64. Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette/Belvaux, Luxembourg.
  • 65. Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain.
  • 66. Instituto Biosanitario de Granada (ibs.Granada), Granada, Spain.
  • 67. Center of Neurology, University Hospital Bonn, University of Bonn, Bonn, Germany.
  • 68. Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, CA, USA.
  • 69. Department of Neurobiology and Behaviour, University of California Irvine, Irvine, CA, USA.
  • 70. Department of Pathology and Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA, USA.
  • 71. Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA.
  • 72. Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA.
  • 73. Faculty of Medicine and Health Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
  • 74. Department of NeuroAnesthesia, University of Illinois at Chicago, Chicago, IL, USA.
  • 75. Department of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK.
  • 76. Department of Molecular Genetics & Microbiology and Neurology, University of New Mexico, Albuquerque, NM, USA.
  • 77. UK Dementia Research Institute, Institute of Neurology, University College London, London, UK.
  • 78. Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • 79. Department of Pharmacology and Chemical Biology, Emory Center for Neurodegenerative Disease, Emory University, Atlanta, GA, USA.
  • 80. Department of Neurology, Emory Center for Neurodegenerative Disease, Emory University, Atlanta, GA, USA.
  • 81. Third Rock Ventures, Boston, MA, USA.
  • 82. Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.
  • 83. Department of Psychiatry, McGill University Faculty of Medicine, Montreal, Québec, Canada.
  • 84. Microglia and Inflammation in Neurological Disorders (MIND) Lab, VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
  • 85. Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
PMID: 39653749 DOI: 10.1038/s41577-024-01104-7
Abstract

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.