Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

The path to next-generation disease-modifying immunomodulatory combination therapies in Alzheimer’s disease

Nature Aging volume 4, pages 761–770 (2024)Cite this article

Subjects

Abstract

The cautious optimism following recent anti-amyloid therapeutic trials for Alzheimer’s disease (AD) provides a glimmer of hope after years of disappointment. Although these encouraging results represent discernible progress, they also highlight the need to enhance further the still modest clinical efficacy of current disease-modifying immunotherapies. Here, we highlight crucial milestones essential for advancing precision medicine in AD. These include reevaluating the choice of therapeutic targets by considering the key role of both central neuroinflammation and peripheral immunity in disease pathogenesis, refining patient stratification by further defining the inflammatory component within the forthcoming ATN(I) (amyloid, tau and neurodegeneration (and inflammation)) classification of AD biomarkers and defining more accurate clinical outcomes and prognostic biomarkers that better reflect disease heterogeneity. Next-generation immunotherapies will need to go beyond the current antibody-only approach by simultaneously targeting pathological proteins together with innate neuroinflammation and/or peripheral–central immune crosstalk. Such innovative immunomodulatory combination therapy approaches should be evaluated in appropriately redesigned clinical therapeutic trials, which must carefully integrate the neuroimmune component.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Role of chronic innate neuroinflammation in AD pathogenesis.
Fig. 2: Next-generation immunomodulatory combination therapies in AD.
Fig. 3: Considering the neuroimmune component in the design of AD immunotherapeutic trials.

Similar content being viewed by others

References

  1. Salloway, S. et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N. Engl. J. Med. 370, 322–333 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Doody, R. S. et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N. Engl. J. Med. 370, 311–321 (2014).

    CAS  PubMed  Google Scholar 

  3. Honig, L. S. et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N. Engl. J. Med. 378, 321–330 (2018).

    CAS  PubMed  Google Scholar 

  4. Ostrowitzki, S. et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res. Ther. 9, 95 (2017).

    PubMed  PubMed Central  Google Scholar 

  5. Egan, M. F. et al. Randomized trial of verubecestat for prodromal Alzheimer’s disease. N. Engl. J. Med. 380, 1408–1420 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Henley, D. et al. Preliminary results of a trial of atabecestat in preclinical Alzheimer’s disease. N. Engl. J. Med. 380, 1483–1485 (2019).

    PubMed  Google Scholar 

  7. Siemers, E. R. et al. Phase 3 solanezumab trials: secondary outcomes in mild Alzheimer’s disease patients. Alzheimers Dement. 12, 110–120 (2016).

    PubMed  Google Scholar 

  8. Fillit, H. & Green, A. Aducanumab and the FDA—where are we now? Nat. Rev. Neurol. 17, 129–130 (2021).

    PubMed  Google Scholar 

  9. van Dyck, C. H. et al. Lecanemab in early Alzheimer’s disease. N. Engl. J. Med. 388, 9–21 (2023).

    PubMed  Google Scholar 

  10. Sims, J. R. et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA 330, 512–527 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Jun, H., Cho, S. K., Yoong, J. & Mattke, S. Is Korea prepared for an Alzheimer’s disease-modifying therapy? Assessing the Korean healthcare system infrastructure and the effect of blood-based biomarker tests. Ann. Geriatr. Med. Res. 25, 33–38 (2021).

    PubMed  PubMed Central  Google Scholar 

  12. Mattke, S. et al. Preparedness of the Brazilian health-care system to provide access to a disease-modifying Alzheimer’s disease treatment. Alzheimers Dement. 19, 375–381 (2023).

    PubMed  Google Scholar 

  13. Leng, F. & Edison, P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat. Rev. Neurol. 17, 157–172 (2021).

    PubMed  Google Scholar 

  14. Bettcher, B. M., Tansey, M. G., Dorothée, G. & Heneka, M. T. Peripheral and central immune system crosstalk in Alzheimer disease—a research prospectus. Nat. Rev. Neurol. 17, 689–701 (2021).

    PubMed  PubMed Central  Google Scholar 

  15. Imbimbo, B. P., Watling, M., Imbimbo, C. & Nisticò, R. Plasma ATN(I) classification and precision pharmacology in Alzheimer’s disease. Alzheimers Dement. 19, 4729–4734 (2023).

    CAS  PubMed  Google Scholar 

  16. Sarazin, M., Dorothée, G., de Souza, L. C. & Aucouturier, P. Immunotherapy in Alzheimer’s disease: do we have all the pieces of the puzzle? Biol. Psychiatry 74, 329–332 (2013).

    CAS  PubMed  Google Scholar 

  17. Holstege, H. et al. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease. Nat. Genet. 54, 1786–1794 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Bellenguez, C. et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat. Genet. 54, 412–436 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Romero-Molina, C., Garretti, F., Andrews, S. J., Marcora, E. & Goate, A. M. Microglial efferocytosis: diving into the Alzheimer’s disease gene pool. Neuron 110, 3513–3533 (2022).

    CAS  PubMed  Google Scholar 

  20. Hamelin, L. et al. Early and protective microglial activation in Alzheimer’s disease: a prospective study using 18F-DPA-714 PET imaging. Brain 139, 1252–1264 (2016).

    PubMed  Google Scholar 

  21. Hamelin, L. et al. Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer’s disease. Brain 141, 1855–1870 (2018).

    PubMed  Google Scholar 

  22. Kunkle, B. W. et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat. Genet. 51, 414–430 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Wightman, D. P. et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease. Nat. Genet. 53, 1276–1282 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Paolicelli, R. C. et al. Microglia states and nomenclature: a field at its crossroads. Neuron 110, 3458–3483 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Escartin, C. et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat. Neurosci. 24, 312–325 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Ulland, T. K. & Colonna, M. TREM2—a key player in microglial biology and Alzheimer disease. Nat. Rev. Neurol. 14, 667–675 (2018).

    CAS  PubMed  Google Scholar 

  27. Schlepckow, K., Morenas-Rodríguez, E., Hong, S. & Haass, C. Stimulation of TREM2 with agonistic antibodies—an emerging therapeutic option for Alzheimer’s disease. Lancet Neurol. 22, 1048–1060 (2023).

    CAS  PubMed  Google Scholar 

  28. Chen, X. & Holtzman, D. M. Emerging roles of innate and adaptive immunity in Alzheimer’s disease. Immunity 55, 2236–2254 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Hartnell, I. J., Blum, D., Nicoll, J. A. R., Dorothee, G. & Boche, D. Glial cells and adaptive immunity in frontotemporal dementia with tau pathology. Brain 144, 724–745 (2021).

    PubMed  Google Scholar 

  30. Laurent, C. et al. Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy. Brain 140, 184–200 (2017).

    PubMed  Google Scholar 

  31. Chen, X. et al. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature 615, 668–677 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Hartnell, I. J. et al. Glial reactivity and T cell infiltration in frontotemporal lobar degeneration with tau pathology. Brain https://doi.org/10.1093/brain/awad309 (2024).

    Article  PubMed  Google Scholar 

  33. Dansokho, C. et al. Regulatory T cells delay disease progression in Alzheimer-like pathology. Brain 139, 1237–1251 (2016).

    PubMed  Google Scholar 

  34. Alves, S. et al. Interleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer’s disease mice. Brain 140, 826–842 (2017).

    PubMed  Google Scholar 

  35. Yuan, L. et al. Low-dose IL-2 treatment rescues cognitive deficits by repairing the imbalance between Treg and Th17 cells at the middle Alzheimer’s disease stage. J. Neuroimmune Pharmacol. https://doi.org/10.1007/s11481-023-10090-x (2023).

    Article  PubMed  Google Scholar 

  36. Stym-Popper, G. et al. Regulatory T cells decrease C3-positive reactive astrocytes in Alzheimer-like pathology. J. Neuroinflammation 20, 64 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Baruch, K. et al. Breaking immune tolerance by targeting Foxp3+ regulatory T cells mitigates Alzheimer’s disease pathology. Nat. Commun. 6, 7967 (2015).

    CAS  PubMed  Google Scholar 

  38. Da Mesquita, S. et al. Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology. Sci. Adv. 7, eabe4601 (2021).

    PubMed  PubMed Central  Google Scholar 

  39. Elyahu, Y. et al. Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes. Sci. Adv. 5, eaaw8330 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Piehl, N. et al. Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment. Cell 185, 5028–5039 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Yuan, Y. et al. Therapeutic potential of interleukin-2 in autoimmune diseases. Trends Mol. Med. 28, 596–612 (2022).

    CAS  PubMed  Google Scholar 

  42. Zhang, H. et al. In vivo expansion of regulatory T cells with IL-2/IL-2 antibody complex protects against transient ischemic stroke. J. Neurosci. 38, 10168–10179 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Webster, K. E. et al. In vivo expansion of T reg cells with IL-2–mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J. Exp. Med. 206, 751–760 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Gao, W. et al. IL-2/anti-IL-2 complex attenuates inflammation and BBB disruption in mice subjected to traumatic brain injury. Front. Neurol. 8, 281 (2017).

    PubMed  PubMed Central  Google Scholar 

  45. Yshii, L. et al. Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation. Nat. Immunol. 23, 878–891 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Lopes, J. R. et al. Nasal administration of anti-CD3 monoclonal antibody ameliorates disease in a mouse model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 120, e2309221120 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Faridar, A. et al. A phase 1 open-label pilot study of low-dose interleukine-2 immunotherapy in patients with Alzheimer’s disease. Transl. Neurodegener. 12, 54 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Baek, H. et al. Neuroprotective effects of CD4+CD25+Foxp3+ regulatory T cells in a 3xTg-AD Alzheimer’s disease model. Oncotarget 7, 69347–69357 (2016).

    PubMed  PubMed Central  Google Scholar 

  49. Faridar, A. et al. Restoring regulatory T-cell dysfunction in Alzheimer’s disease through ex vivo expansion. Brain Commun. 2, fcaa112 (2020).

    PubMed  PubMed Central  Google Scholar 

  50. Yang, H. et al. Adoptive therapy with amyloid-β specific regulatory T cells alleviates Alzheimer’s disease. Theranostics 12, 7668–7680 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Yeapuri, P. et al. Amyloid-β specific regulatory T cells attenuate Alzheimer’s disease pathobiology in APP/PS1 mice. Mol. Neurodegener. 18, 97 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Saetzler, V. et al. Development of β-amyloid-specific CAR-Tregs for the treatment of Alzheimer’s disease. Cells 12, 2115 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Baruch, K. et al. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer’s disease. Nat. Med. 22, 135–137 (2016).

    CAS  PubMed  Google Scholar 

  54. Rosenzweig, N. et al. PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat. Commun. 10, 465 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Latta-Mahieu, M. et al. Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-β burden in several amyloid transgenic mouse models. Glia 66, 492–504 (2018).

    PubMed  Google Scholar 

  56. Kummer, M. P. et al. Microglial PD-1 stimulation by astrocytic PD-L1 suppresses neuroinflammation and Alzheimer’s disease pathology. EMBO J. 40, e108662 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Kim, K. et al. Therapeutic B-cell depletion reverses progression of Alzheimer’s disease. Nat. Commun. 12, 2185 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Wolf, S. D., Dittel, B. N., Hardardottir, F. & Janeway, C. A. Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J. Exp. Med. 184, 2271–2278 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Jack, C. R. et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 14, 535–562 (2018).

    PubMed  Google Scholar 

  60. Jutten, R. J. et al. Finding treatment effects in Alzheimer trials in the face of disease progression heterogeneity. Neurology 96, e2673–e2684 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Bernick, C., Cummings, J., Raman, R., Sun, X. & Aisen, P. Age and rate of cognitive decline in Alzheimer disease: implications for clinical trials. Arch. Neurol. 69, 901–905 (2012).

    PubMed  Google Scholar 

  62. Olivieri, P. et al. Characterization of the initial complaint and care pathways prior to diagnosis in very young sporadic Alzheimer’s disease. Alzheimers Res. Ther. 13, 90 (2021).

    PubMed  PubMed Central  Google Scholar 

  63. Lagarde, J. et al. Tau-PET imaging predicts cognitive decline and brain atrophy progression in early Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 93, 459–467 (2022).

    PubMed  Google Scholar 

  64. Mintun, M. A. et al. Donanemab in early Alzheimer’s disease. N. Engl. J. Med. 384, 1691–1704 (2021).

    CAS  PubMed  Google Scholar 

  65. Groot, C. et al. Diagnostic and prognostic performance to detect Alzheimer’s disease and clinical progression of a novel assay for plasma p-tau217. Alzheimers Res. Ther. 14, 67 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Dujardin, S. et al. Tau molecular diversity contributes to clinical heterogeneity in Alzheimer’s disease. Nat. Med. 26, 1256–1263 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Dong, Y. et al. Neutrophil hyperactivation correlates with Alzheimer’s disease progression. Ann. Neurol. 83, 387–405 (2018).

    CAS  PubMed  Google Scholar 

  68. Manly, J. J. & Deters, K. D. Donanemab for Alzheimer disease—who benefits and who is harmed? JAMA 330, 510–511 (2023).

    PubMed  Google Scholar 

  69. Livingston, G. et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 396, 413–446 (2020).

    PubMed  PubMed Central  Google Scholar 

  70. Liu, K. Y. et al. Evaluation of clinical benefits of treatments for Alzheimer’s disease. Lancet Healthy Longev. 4, e645–e651 (2023).

    PubMed  Google Scholar 

  71. Salloway, S. et al. Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease. JAMA Neurol. 79, 13–21 (2022).

    PubMed  Google Scholar 

  72. Budd Haeberlein, S. et al. Two randomized phase 3 studies of aducanumab in early Alzheimer’s disease. J. Prev. Alzheimers Dis. 9, 197–210 (2022).

    CAS  PubMed  Google Scholar 

  73. Cummings, J. et al. Lecanemab: appropriate use recommendations. J. Prev. Alzheimers Dis. 10, 362–377 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Chantran, Y. et al. Letter to the editor: serum anti-Aβ antibodies in cerebral amyloid angiopathy. Autoimmun. Rev. 20, 102870 (2021).

    PubMed  Google Scholar 

  75. Alves, F., Kalinowski, P. & Ayton, S. Accelerated brain volume loss caused by anti-β-amyloid drugs: a systematic review and meta-analysis. Neurology 100, e2114–e2124 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Alexander, G. C., Emerson, S. & Kesselheim, A. S. Evaluation of aducanumab for Alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility. JAMA 325, 1717–1718 (2021).

    PubMed  Google Scholar 

  77. Liu, K. Y. & Howard, R. Can we learn lessons from the FDA’s approval of aducanumab? Nat. Rev. Neurol. 17, 715–722 (2021).

    PubMed  Google Scholar 

  78. Alexander, G. C. et al. Revisiting FDA approval of aducanumab. N. Engl. J. Med. 385, 769–771 (2021).

    CAS  PubMed  Google Scholar 

  79. de Souza, L. C. et al. Similar amyloid-β burden in posterior cortical atrophy and Alzheimer’s disease. Brain 134, 2036–2043 (2011).

    PubMed  Google Scholar 

  80. Rabinovici, G. D. et al. Increased metabolic vulnerability in early-onset Alzheimer’s disease is not related to amyloid burden. Brain 133, 512–528 (2010).

    PubMed  PubMed Central  Google Scholar 

  81. Ikonomovic, M. D. et al. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease. Brain 131, 1630–1645 (2008).

    PubMed  PubMed Central  Google Scholar 

  82. Moloney, C. M., Lowe, V. J. & Murray, M. E. Visualization of neurofibrillary tangle maturity in Alzheimer’s disease: a clinicopathologic perspective for biomarker research. Alzheimers Dement. 17, 1554–1574 (2021).

    CAS  PubMed  Google Scholar 

  83. Lagarde, J. et al. Could tau-PET imaging contribute to a better understanding of the different patterns of clinical progression in Alzheimer’s disease? A 2-year longitudinal study. Alzheimers Res. Ther. 15, 91 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

G.D. is funded by the Agence Nationale de la Recherche (grant ANR-21-CE17-0054-01), the Fondation Alzheimer, the Fondation pour la Recherche Médicale and the Fondation Pierre Deniker. G.D. and B.B. are funded by the Association France Alzheimer, the Fondation Vaincre Alzheimer and Sorbonne University. M.S., J.L. and M.B. are funded by the Fondation Alzheimer, the Fondation Recherche Alzheimer, the Association France Alzheimer, the Fondation pour la Recherche Médicale and the French Ministry of Health (grants PHRC-2010-0054-N and PHRC-2013-0919).

Author information

Author notes

  1. These authors contributed equally: Marie Sarazin, Julien Lagarde, Guillaume Dorothée.

Authors and Affiliations

  1. Department of Neurology of Memory and Language, GHU Paris Psychiatrie & Neurosciences, Hôpital Sainte-Anne, Paris, France

    Marie Sarazin & Julien Lagarde

  2. Université Paris-Cité, Paris, France

    Marie Sarazin & Julien Lagarde

  3. Université Paris-Saclay, BioMaps, Service Hospitalier Frédéric Joliot, CEA, CNRS, Inserm, Orsay, France

    Marie Sarazin, Julien Lagarde & Michel Bottlaender

  4. Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Immune System and Neuroinflammation Laboratory, Hôpital Saint-Antoine, Paris, France

    Inès El Haddad, Bertrand Bellier & Guillaume Dorothée

  5. Grupo de Pesquisa em Neurologia Cognitiva e do Comportamento, Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil

    Leonardo Cruz de Souza

  6. Programa de Pós-Graduação em Neurociências, UFMG, Belo Horizonte, Brazil

    Leonardo Cruz de Souza

  7. Departamento de Clínica Médica, Faculdade de Medicina, UFMG, Belo Horizonte, Brazil

    Leonardo Cruz de Souza

  8. Paris Brain Institute (ICM), Centre National de la Recherche Scientifique (CNRS) UMR 7225, INSERM U1127, Hôpital de la Pitié-Salpêtrière, Sorbonne Université, Paris, France

    Marie-Claude Potier

  9. Université Paris-Saclay, UNIACT, Neurospin, Joliot Institute, CEA, Gif-sur-Yvette, France

    Michel Bottlaender

Authors
  1. Marie Sarazin
    View author publications

    Search author on:PubMed Google Scholar

  2. Julien Lagarde
    View author publications

    Search author on:PubMed Google Scholar

  3. Inès El Haddad
    View author publications

    Search author on:PubMed Google Scholar

  4. Leonardo Cruz de Souza
    View author publications

    Search author on:PubMed Google Scholar

  5. Bertrand Bellier
    View author publications

    Search author on:PubMed Google Scholar

  6. Marie-Claude Potier
    View author publications

    Search author on:PubMed Google Scholar

  7. Michel Bottlaender
    View author publications

    Search author on:PubMed Google Scholar

  8. Guillaume Dorothée
    View author publications

    Search author on:PubMed Google Scholar

Contributions

All authors contributed to researching data and literature related to the article, discussing its content, and writing, reviewing and/or editing the manuscript.

Corresponding authors

Correspondence to Marie Sarazin or Guillaume Dorothée.

Ethics declarations

Competing interests

G.D. is listed as an inventor on one patent and one patent application, both on Treg-based immunomodulatory treatments in AD and other tauopathies. G.D. served on the scientific advisory board of Coya Therapeutics and received lecturer fees from Eisai. G.D. and M.S. received research support from Institut Roche. L.C.d.S. participated in the advisory board for Biogen and as speaker in symposia sponsored by Biogen. The other authors declare no competing interests.

Peer review

Peer review information

Nature Aging thanks Marie-Victoire Guillot-Sestier, Alon Monsonego and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sarazin, M., Lagarde, J., El Haddad, I. et al. The path to next-generation disease-modifying immunomodulatory combination therapies in Alzheimer’s disease. Nat Aging 4, 761–770 (2024). https://doi.org/10.1038/s43587-024-00630-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s43587-024-00630-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing