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Cited by 638Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Neuroinflammation in Alzheimer disease

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Heneka, Michael T., van der Flier, Wiesje M., Jessen, Frank, Hoozemanns, Jeroen, Thal, Dietmar Rudolf, Boche, Delphine, Brosseron, Frederic, Teunissen, Charlotte +63 more·2025·Nature Reviews Immunology
DOI 10.1038/s41577-024-01104-7PMC PMC13148177
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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.

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  • AD is neuropathologically characterized by accumulation of extracellular amyloid-β plaques and intracellular tau tangles, leading to synaptic dysfunction and progressive neuronal loss.

    “AD is neuropathologically characterized by the accumulation of extracellular amyloid-ß plaques and intracellular tau tangles, leading to synaptic dysfunction and progressive neuronal loss [22].”

    From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [22]

    The Introduction identifies extracellular amyloid-β deposits and intraneuronal tau tangles as neuropathological features of AD. The “Synapses and axons” section describes synapse loss and dysfunction in amyloid-β and tau models, and “Microglial senescence” discusses tau-mediated neurodegeneration. These passages do not establish the sentence’s broader, direct claim that plaque and tangle accumulation leads to progressive neuronal loss in AD. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Genome-wide association studies have consistently implicated immune-related pathways in AD susceptibility, particularly those involving microglial function.

    “Genome-wide association studies have consistently implicated immune-related pathways in AD susceptibility, particularly those involving microglial function [21,22].”

    From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [22]

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References 604 · Cited by 638

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200 of 424 shown

Authors
Heneka, M. T., van der Flier, W. M., Jessen, F., Hoozemanns, J., Thal, D. R., Boche, D., Brosseron, F., Teunissen, C., Zetterberg, H., Jacobs, A. H., Edison, P., Ramirez, A., Cruchaga, C., Lambert, J.-C., Laza, A. R., Sanchez-Mut, J. V., Fischer, A., Castro-Gomez, S., Stein, T. D., Kleineidam, L., Wagner, M., Neher, J. J., Cunningham, C., Singhrao, S. K., Prinz, M., Glass, C. K., Schlachetzki, J. C. M., Butovsky, O., Kleemann, K., De Jaeger, P. L., Scheiblich, H., Brown, G. C., Landreth, G., Moutinho, M., Grutzendler, J., Gomez-Nicola, D., McManus, R. M., Andreasson, K., Ising, C., Karabag, D., Baker, D. J., Liddelow, S. A., Verkhratsky, A., Tansey, M., Monsonego, A., Aigner, L., Dorothée, G., Nave, K.-A., Simons, M., Constantin, G., Rosenzweig, N., Pascual, A., Petzold, G. C., Kipnis, J., Venegas, C., Colonna, M., Walter, J., Tenner, A. J., O’Banion, M. K., Steinert, J. R., Feinstein, D. L., Sastre, M., Bhaskar, K., Hong, S., Schafer, D. P., Golde, T., Ransohoff, R. M., Morgan, D., Breitner, J., Mancuso, R., & Riechers, S.-P.
Affiliations
  • University of Luxembourg (LU)
  • University of Cologne (DE)
  • Universitair Ziekenhuis Leuven (BE)
  • University of Southampton (GB)
  • German Center for Neurodegenerative Diseases (DE)
  • Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
  • University of Gothenburg (SE)
  • University of Münster (DE)
  • Imperial College London (GB)
  • Washington University in St. Louis (US)
  • Inserm (FR)
  • Consejo Superior de Investigaciones Científicas (ES)
  • Boston University (US)
  • University of Bonn (DE)
  • Trinity College Dublin (IE)
  • University of Lancashire (GB)
  • University of Freiburg (DE)
  • University of California San Diego (US)
  • Brigham and Women's Hospital (US)
  • University of Cambridge (GB)
  • Indiana University Indianapolis (US)
  • Yale University (US)
  • Stanford Medicine (US)
  • Mayo Clinic (US)
  • New York University (US)
  • University of Manchester (GB)
  • Ben-Gurion University of the Negev (IL)
  • Paracelsus Medical University (AT)
  • Max Planck Institute for Multidisciplinary Sciences (DE)
  • Technical University of Munich (DE)
  • University of Verona (IT)
  • Instituto de Biomedicina de Sevilla (ES)
  • Universidad de Granada (ES)
  • University of California, Irvine (US)
  • University of Rochester Medicine (US)
  • University of Nottingham (GB)
  • University of Illinois Chicago (US)
  • Hammersmith Hospital (GB)
  • University of New Mexico (US)
  • UK Dementia Research Institute (GB)
  • University of Massachusetts Chan Medical School (US)
  • Emory University (US)
  • Michigan State University (US)
  • McGill University (CA)
  • University of Antwerp (BE)
Corresponding author
Heneka, Michael T.
ORCID
Venue
Nature Reviews Immunology
Publisher
Springer Science and Business Media LLC
Published
2024-12-09
Volume
25
Issue
5
Pages
321-352
ISSN
  • 1474-1733 (ISSN-L)
  • 1474-1741
DOI
10.1038/s41577-024-01104-7
PMC
PMC13148177
OpenAlex
W4405187546
Cited by
638
References
604
Citations by year
2026: 402 · 2025: 236
FWCI
30.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature reviews. Immunology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
  • CLOK (University of Central Lancashire) (acceptedVersion)
  • Pure Amsterdam UMC (acceptedVersion, other-oa)
  • IUScholarWorks (Indiana University) (submittedVersion)
  • ePrints Soton (University of Southampton) (submittedVersion)
  • Lirias (submittedVersion, other-oa)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
  • Repository@Nottingham (University of Nottingham) (submittedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
  • Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
  • DZNE Pub (submittedVersion)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
  • National Aeronautics and Space Administration (80NSSC21K0542)
  • U.S. Department of Veterans Affairs (IK6BX004852)
  • Alzheimer's Association (ABA-22-968700, 22HLT07, 2022-01018, 24AARF-1243474, E2A-23-1148152, PE0000006, 22-AAIIA-963171, 2019-02397)
  • Glenn Foundation for Medical Research
  • Eli Lilly and Company
  • Pfizer
  • Sanofi
  • Biogen
  • Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
  • BrightFocus Foundation (2020A016806, A2021034S, A2021035S)
  • Alnylam Pharmaceuticals
  • Danone
  • Alzheimer Forschung Initiative (390857198, Grant 21060, 2021-1A-12, 21060)
  • EU Joint Programme – Neurodegenerative Disease Research
  • Fondation Vaincre Alzheimer
  • Chan Zuckerberg Initiative
  • Prothena
  • Health~Holland (#LSHM20106)
  • Alzheimer's Society
  • Roche Nederland
  • Apellis Pharmaceuticals
  • European Commission (-71320, 22HLT07, 390857198, PE0000006, 101034344, 101,053,962, 831434, HORIZON2020, MCIN / AEI/10, ALFGBG-71320, 860197, 2022-2025)
  • Deutsche Forschungsgemeinschaft (SFB1454, EXC 2145, 432325352, TRR-274, EXC 2145SyNergy, EXC 2067, EXC2151390873048, 390857198, EXC 2151, EXC 2067‐1, 390729940, EXC 2067/1390729940, 390873048)
  • Agence Nationale de la Recherche (2020/2021, ANR-21-CE17-0054, ANR-24-CE18-2770)
  • Fondation Leducq (390857198, 23CVD03, EXC 2067/1)
  • ZonMw (10510032120003, LSHM20106, 432325352, #73305095007)
  • Irish Research Council
  • Austrian Science Fund (35417-B, P 35417)
  • Fondation pour la Recherche Médicale
  • Fonds Wetenschappelijk Onderzoek (G065721N, 22-AAIIA-963171, G0C9219N, G0K9422N, 2023/0009, G056022N, 2022-2025)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (#73305095007, 21060)
  • Nuclear Safety and Security Commission
  • Association France Alzheimer
  • Eisai
  • Novo Nordisk
  • Vetenskapsrådet (#101053962, 860197, 2022-01018, ALFGBG‐71320, 2023-00356, 2019-02397, 2018-)
  • Universiteit Antwerpen
  • Fondation Pierre Deniker pour la Recherche et la Prévention en Santé Mentale
  • Hersenstichting
  • Stichting Dioraphte
  • Alzheimer Nederland (LSHM20106)
  • Siemens Healthineers
  • Vlaamse regering
  • Ono Pharmaceutical
  • FONDATION ALZHEIMER
  • UK Dementia Research Institute (UKDRI‐1011)
  • Amsterdam Neuroscience
  • European Brain Council
  • GIESKES-STRIJBIS FONDS
  • National Institutes of Health (18.04, AG054349, R24OD036199)
  • Avid Radiopharmaceuticals
  • Wu Tsai Neurosciences Institute, Stanford University
  • HORIZON EUROPE Framework Programme (PE0000006, 101053962, 860197, 2020/2021)
  • Medical Research Council (MR/Y004116/1, MR/P024572/1)
  • Agencia Estatal de Investigación (13039, MCIN / AEI/10, AEI/10)
  • National Institute on Aging (R41AG073059, AG077651, AG072931, R21AG076982, AG055072, R01AG051812, AG054349, RF1AG068281, R01AG053229, R01AG068076, AG051812, R01AG054672, P30AG072931, U54AG079779, U54AG054349, P30AG086404)
  • National Institute of Neurological Disorders and Stroke (RF1NS083704, R01NS117533, R01NS088137)
  • National Institute of Environmental Health Sciences (P30ES027792)
  • HORIZON EUROPE European Research Council (101041867)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
Alzheimer's disease, neuroinflammation, innate immunity, adaptive immunity, microglia, neurodegeneration, dementia, genetic risk factors, lifestyle factors, traumatic brain injury, infection, vascular inflammation, anti-inflammatory agents
MeSH terms
Neuroinflammatory Diseases, Alzheimer Disease, Animals, Humans, Immunity, Innate, Inflammation

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