Immune dysfunction in Alzheimer disease

Oleg Butovsky; Neta Rosenzweig; Kilian L Kleemann; Mehdi Jorfi; Vijay K Kuchroo; Rudolph E Tanzi; Howard L Weiner

doi:10.1038/s41583-025-00997-0

Immune dysfunction in Alzheimer disease

Nat Rev Neurosci. 2025 Nov 28. doi: 10.1038/s41583-025-00997-0. Online ahead of print.

Authors

Oleg Butovsky^{1

2}, Neta Rosenzweig³, Kilian L Kleemann^{3

4}, Mehdi Jorfi⁵, Vijay K Kuchroo^{3

6}, Rudolph E Tanzi⁵, Howard L Weiner^{3

6}

Affiliations

¹ Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. obutovsky@bwh.harvard.edu.
² Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Mass General Hospital, Boston, MA, USA. obutovsky@bwh.harvard.edu.
³ Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
⁵ Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease and Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
⁶ Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Mass General Hospital, Boston, MA, USA.

PMID: 41315874
DOI: 10.1038/s41583-025-00997-0

Abstract

Emerging evidence highlights the crucial role of peripheral immune cells in maintaining brain homeostasis and their influence on the pathology of Alzheimer disease (AD). Genome-wide association studies have identified numerous AD risk variants in genes expressed by immune cells, implicating innate and adaptive immune pathways in disease progression. Advances in neuroimmunology have revealed that immune cell crosstalk involving T cells, B cells, monocytes and/or macrophages and neutrophils can modulate the hallmark features of AD, including amyloid plaque accumulation, tau pathology and chronic neuroinflammation. Mechanistic insights suggest that chronic peripheral inflammation, immune exhaustion, metabolic dysfunction and epigenetic reprogramming exacerbate neurodegeneration in AD by promoting toxic inflammation and impairing protein clearance in the brain. These findings may catalyse the development of novel immunomodulatory strategies, such as immune checkpoint inhibition and cytokine targeting, among others, for AD. This Review examines peripheral immune alterations in AD, evaluates related therapeutic opportunities and highlights key knowledge gaps, particularly the need for human-derived data to advance translational progress. Future research should prioritize personalized approaches that integrate genetic risk, immune profiling and ageing to inform next-generation therapies for AD.

Publication types

Review