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Therapeutic targeting of neuroimmune mechanisms in neurodegeneration

Nature Reviews Drug Discovery (2026)Cite this article

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Abstract

Effective treatments for age-related chronic neurodegenerative diseases such as Alzheimer’s disease remain limited, in part because the molecular drivers of cognitive decline are still not fully understood. Human genetic studies, together with detailed analysis of disease pathology, indicate that the immune system has an important influence on disease progression. Research to date has focused largely on microglia — specialized innate immune cells that reside within the central nervous system (CNS) — as functional studies combined with deep transcriptional profiling have improved our understanding of this innate immune cell type in neurodegeneration and have identified several potential therapeutic targets. Increasing evidence now shows that microglia coordinate diverse CNS and peripheral cell populations to shape disease outcomes. In this Review, we discuss these neuroimmune interactions, which reveal a more intricate framework for how the central and peripheral immune systems may influence neurodegeneration. These insights could redirect future drug discovery efforts towards immune targets that complement existing therapies aimed at core pathological features. We also outline how this knowledge suggests new therapeutic strategies and highlight a critical need for disease-specific neuroimmune biomarkers.

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Fig. 1: CNS-resident, vascular and peripheral immune cell types express AD risk factors.
Fig. 2: Cellular interactions of AD genetic risk factors define disease-relevant pathways.
Fig. 3: Immune cells at brain barriers coordinate surveillance and signalling.
Fig. 4: Mechanism of action for anti-amyloid antibodies and impact on microglia.
Fig. 5: Therapeutic rationale of combination dosing of anti-amyloid and microglia-targeting mAbs.

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Acknowledgements

The authors thank S. V. Andrews for contributing expertise in interpreting and characterizing human genetics data. The authors also thank colleagues, especially C. Koth, for the extraordinary feedback on this manuscript during conceptualization and writing phases. S.H. is supported by the UK Dementia Research Institute (UKDRI-1011) through UK DRI Ltd, principally funded by the UK Medical Research Council, Chan Zuckerberg Initiative Neurodegeneration Challenge Network, BrightFocus Foundation (A2021032S), Alzheimer’s Association, Alzheimer’s Society UK and the Anonymous Foundation. A.C.Y. is supported by the Cure Alzheimer’s Fund, BrightFocus Foundation, Alzheimer’s Association and NIH Director’s Early Independence Award (1DP5OD033381).

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Authors and Affiliations

  1. Denali Therapeutics Inc., South San Francisco, CA, USA

    Kathryn M. Monroe & Joseph W. Lewcock

  2. UK Dementia Research Institute, University College London, London, UK

    Soyon Hong

  3. Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA

    Andrew C. Yang

  4. Department of Neurology, University of California San Francisco, San Francisco, CA, USA

    Andrew C. Yang

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  1. Kathryn M. Monroe
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  2. Soyon Hong
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  3. Joseph W. Lewcock
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  4. Andrew C. Yang
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Contributions

K.M.M. researched data for the article and contributed substantially to the discussion of the content. All authors wrote and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Kathryn M. Monroe.

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Competing interests

K.M.M. and J.W.L. are full-time employees and shareholders of Denali Therapeutics Inc. S.H. has been a paid consultant for Eisai Ltd, Novo Nordisk and Alnylam; receives research funding from AstraZeneca and Eisai Ltd; and collaborates with Ionis Ltd.

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Glossary

Aicardi–Goutières syndrome

A genetic leukodystrophy in which the immune system damages the myelin sheaths that protect neurons in the brain and spinal cord; symptoms include neurological defects such as developmental regression, seizures, microcephaly and poor feeding behaviour.

Amyloid mouse model

A mouse strain that develops amyloid plaque deposition in the brain, a hallmark pathology of the Alzheimer’s disease (AD), driven by genetic modification of amyloid precursor protein (APP) with one or more mutations found in human disease.

Amyloid-related imaging abnormalities

(ARIA). Defined using MRI and caused by disruption of blood vessels in the brain with amyloid deposition; the risk of ARIA is increased with some anti-amyloid antibody therapies.

Astrocyte end-feet

Processes that extend from astrocytes that ensheathe blood vessels and provide structural integrity to the vasculature in the brain.

Cerebral amyloid angiopathy

(CAA). A type of cerebrovascular disease characterized by amyloid deposition with cerebral blood vessels that can lead to cognitive impairment, microbleeds and other neurological symptoms.

Glia limitans

The outermost barrier of the CNS parenchyma, formed by astrocyte end-feet and a basement membrane that ensheathes the brain surface and lines perivascular spaces wherein it functions as a secondary checkpoint behind the endothelial blood–brain barrier.

Neuromyelitis optica spectrum disorder

An autoimmune disease in which optic nerve and spinal cord are damaged by autoantibodies; symptoms include vision loss, pain, numbness, weakness and paralysis that can worsen over time.

Pericytes

Cells that wrap around blood vessel walls and contribute to blood–brain barrier integrity and regulate blood flow.

Synaptic engulfment

The selective removal of synapses that mediate neuronal signalling; this process is mediated by microglia via the complement pathway during normal development of the CNS and during disease.

Tauopathy mouse model

A mouse strain that recapitulates tau pathology that occurs in neurodegenerative diseases including frontotemporal dementia (FTD) and AD; tangles of tau protein form in neurons and interfere with their health and function.

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Monroe, K.M., Hong, S., Lewcock, J.W. et al. Therapeutic targeting of neuroimmune mechanisms in neurodegeneration. Nat Rev Drug Discov (2026). https://doi.org/10.1038/s41573-025-01370-7

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