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Distinct amyloid-β and tau-associated microglia profiles in Alzheimer’s disease
Open accessAbstract
Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-β and intraneuronal hyperphosphorylated tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-β and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-β plaques or both amyloid-β plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-β load and localized to amyloid-β plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with overt tau pathology. This full characterization of human disease-associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.
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![Fig. 3 AD1-microglia subclusters gradually transition towards a phagocytic/activated profile. a UMAPs depicting trajectory analysis of homeostatic and AD1-subclusters. Color-scale indicates pseudotime, subclusters and expression of CX3CR1 (homeostasis) and MYO1E (AD1). b Density heatmaps depicting the distribution of nuclei over the UMAP for each sample group. c Violin plots depicting expression of selected genes per subcluster. *: genes significantly differentially expressed (Moran’s I test, q-value < 0.05). d Heatmap depicting all genes significantly differentially expressed over the trajectory *: Moran’s I test, q-value < 0.05). e Heatmaps depicting top 40 (non-ribosomal) DAM genes from [18] and top 37 (non-ribosomal) ARM genes from [30] over pseudotime. *: Moran’s I test, q-value < 0.05. f IBA1, P2RY12, and ITGAX co-expression in tissues from a CTR and an AD donor. Tissue core diameter = 1 mm. g Left: Microglia expressing P2RY12 and IBA1, but not ITGAX. Right: Microglia expressing IBA1 and ITGAX, but not P2RY12. Microglia are from the tissue section and exist next to each other. Scale bar = 20 μm. h Left: Gene expression of P2RY12 (green) and ITGAX (pink) along the trajectory. Right: Correlation between % P2RY12pos area and % ITGAXpos area per sample. OC Occipital Cortex; OTC Occipitotemporal Cortex; CTR non-demented controls; CTR+ non-demented controls with mild amyloid-β pathology; AD clinical and neuropathological Alzheimer’s disease; PD Parkinson’s disease; LB Lewy body dementia](/paper-figures/5d835a6601374e458c5683660903fe52/distinct-amyloid-and-tau-associated-microglia-profiles-in-alzheimers-disease-figure-3.jpg)
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“a population of clusters, namely AD1, closely reassembled the mouse DAM/MGnD phenotype, it was only abundant in human samples containing Aβ and not tau”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [119]
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“Together this work demonstrates, firstly, that there exist other microglial subsets in AD besides the DAM/MGnD phenotype, and secondly, that human microglia are heterogenous, thus limiting the translation of the DAM signature from animal models.”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [119]
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“These findings were not formally published, however two recent reports suggest the presence of B cells in the brains of patients with AD [81,82].”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [82]
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“A study using singlenucleus RNA sequencing identified a cluster of lymphocytes in AD brains enriched for the expression of IL-7R and MS4A1 genes, which encode the interleukin-7 receptor and CD20 respectively, both estab lished markers of B lymphocytes [82].”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [82]
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“There was considerable overlap between the Micro_D profile and previously reported microglial states, such as the MIMS-foamy state reported in ref. 11, amyloid-associated microglia in Alzheimer’s disease43,46,47 and lipid-associated macrophages (LAMs) in obesity48 (Extended Data Fig. 8).”
From Foamy microglia link oxylipins to disease progression in multiple sclerosis (2026) · cites this paper as [46]
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“The foamy, GPNMB+ microglial phenotype in MS lesions bears striking transcriptional similarity to LAMs in obesity, amyloid-responsive microglia in Alzheimer’s disease and foam cells in atherosclerosis18,46,48,50,51.”
From Foamy microglia link oxylipins to disease progression in multiple sclerosis (2026) · cites this paper as [46]
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“single nuclei RNA sequencing on AD brains showed that out of seven cell types, gene expression changes were shown only in microglia [119]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [119]
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“AD2 did not overlap with AD1 and was more frequently observed in human brain samples showing both tau and amyloid pathology [119]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [119]
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“single cell nuclei extraction from frozen human brain tissue revealed 13 distinct microglial clusters [119]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [119]
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“Moreover, distinct Aβ and tau-associated microglia signatures have been discovered in AD patients.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [15]
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Citations
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Metadata
- Authors
- Gerrits, E., Brouwer, N., Kooistra, S. M., Woodbury, M. E., Vermeiren, Y., Lambourne, M., Mulder, J., Kummer, M., Möller, T., Biber, K., Dunnen, W. F. A. D., De Deyn, P. P., Eggen, B. J. L., & Boddeke, E. W. G. M.
- Affiliations
- University Medical Center Groningen (NL)
- AbbVie (United States) (US)
- Karolinska Institutet (SE)
- AbbVie (Germany) (DE)
- University of Copenhagen (DK)
- Corresponding author
- Boddeke, Erik W. G. M.
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2021-02-20
- Volume
- 141
- Issue
- 5
- Pages
- 681-696
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC8043951
- OpenAlex
- W3129453843
- Cited by
- 441
- References
- 42
- Citations by year
- 2026: 69 · 2025: 80 · 2024: 124 · 2023: 53 · 2022: 87 · 2021: 27
- FWCI
- 30.05
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
- Socio-Environmental Systems Modeling (acceptedVersion, cc-by)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- Funders
- Rijksuniversiteit Groningen
- Stichting MS Research
- Fonds Wetenschappelijk Onderzoek (12Z1620N)
- Universitair Medisch Centrum Groningen
- Vlaamse Instelling voor Technologisch Onderzoek
- Alzheimer Nederland
- Vlaamse regering
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, microglia, amyloid plaques, tau pathology, microglial activation, microglial phenotype, single-nucleus RNA sequencing, phosphorylated tau, disease-associated microglia, microglia-targeted therapy
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Humans, Male, Amyloid beta-Peptides, tau Proteins, Microglia
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