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Microglial phagocytosis in Alzheimer disease

Nature Reviews Neurology volume 22, pages 54–69 (2026)Cite this article

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Abstract

Accumulating evidence indicates that Alzheimer disease (AD) is caused by dysregulated microglial phagocytosis. The main risk factor for AD is age, and ageing reduces microglial phagocytosis of amyloid-β (Aβ) plaques, while increasing microglial phagocytosis of synapses and neurons. Most of the known genetic risk for AD can be linked to microglial phagocytosis, including ABCA1, ABI3, ACE, ADAM17, APOE, APP, BIN1, BLNK, CD2AP, CD33, CLU, CR1, CTSB, CTSH, EED, GRN, INPP5D, LILRB2, PICALM, PLCG2, PSEN1, PTK2B, SIGLEC11, SORL1, SPI1, TMEM106B and TREM2. Moreover, the only disease-modifying treatments for AD — anti-Aβ antibodies — work by increasing microglial phagocytosis of Aβ aggregates. Microglial phagocytosis of Aβ via TREM2, LRP1, CD33, TAM receptors and anti-Aβ antibodies appears to reduce AD pathology by pruning and compacting plaques, restricting subsequent tau pathology, whereas microglial phagocytosis of synapses and neurons seems detrimental in the later stages of AD, via complement, P2Y6 receptor and TREM2. However, the roles of microglial phagocytosis in AD are complex and multifaceted, and improved treatments are likely to require a deeper understanding of these roles.

Key points

  • Insufficient microglial phagocytosis of amyloid-β (Aβ) and/or excessive phagocytosis of synapses and neurons might underly Alzheimer disease (AD) pathology.

  • Most of the known genetic risk for AD is via genes that affect microglial phagocytosis.

  • Increase of microglial phagocytosis of Aβ aggregates using anti-Aβ antibodies clears amyloid plaques and slows AD progression in people with the disease.

  • Microglial phagocytosis of Aβ via antibodies, TREM2, LRP1 and TAM receptors is protective in AD animal models by pruning and compacting plaques.

  • Microglial phagocytosis of synapses and neurons, via complement, P2Y6 receptor and TREM2, is detrimental in AD animal models.

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Fig. 1: Roles of microglial phagocytosis in Alzheimer disease.
Fig. 2: Receptors and signalling involved in microglial phagocytosis of Aβ plaques, synapses and neurons.
Fig. 3: Microglial phagocytosis of synaptic components and neurons.
Fig. 4: AD risk genes and processes involved in microglial phagocytosis.

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Acknowledgements

P.St.G.-H. is supported by grants from the Canadian Institutes of Health Research (406915 Foundation Grant and Canadian Consortium on Neurodegeneration in Aging Grant), National Institute of Aging (grant nos. U01AG072572 and R01AG070864 to P.St.G.-H.). G.L. was supported by a grant from the National Institute of Aging (grant no. RF1AG060748). G.C.B. was funded by the Medical Research Council UK (grant no. MR/L010593), Alzheimer’s Research UK (Dementia Consortium Grant ARUK-DC2017-4, Network Grant G-102212) and the Wellcome Trust (Wellcome Institutional Partnership Award 222062/Z/20/Z). R.C.P. is supported by the Dementia Research Synapsis Foundation, by grants from the Swiss National Science Foundation (grant no. 310030_197940), the European Union Joint Programme — Neurodegenerative Disease Research (grant no. 31ND3O-2L3462), the European Research Area Network (grant no. 31NE30_219096) and funding from the University of Lausanne.

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Authors and Affiliations

  1. Department of Biochemistry, University of Cambridge, Cambridge, UK

    Guy C. Brown

  2. Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    Peter St George-Hyslop

  3. Department of Neurology, Columbia University, New York, NY, USA

    Peter St George-Hyslop

  4. Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland

    Rosa C. Paolicelli

  5. Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA

    Greg Lemke

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Correspondence to Guy C. Brown.

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Brown, G.C., St George-Hyslop, P., Paolicelli, R.C. et al. Microglial phagocytosis in Alzheimer disease. Nat Rev Neurol 22, 54–69 (2026). https://doi.org/10.1038/s41582-025-01162-y

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