Somatic cancer driver mutations are enriched and associated with inflammatory states in Alzheimer’s disease microglia
Open accessAbstract
Summary: Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder characterized by progressive neuronal loss and pathological accumulation of the misfolded proteins amyloid-β and tau 1,2 . Neuroinflammation mediated by microglia and brain-resident macrophages plays a crucial role in AD pathogenesis 1–5 , though the mechanisms by which age, genes, and other risk factors interact remain largely unknown. Somatic mutations accumulate with age and lead to clonal expansion of many cell types, contributing to cancer and many non-cancer diseases 6,7 . Here we studied somatic mutation in normal aged and AD brains by three orthogonal methods and in three independent AD cohorts. Analysis of bulk RNA sequencing data from 866 samples from different brain regions revealed significantly higher (∼two-fold) overall burdens of somatic single-nucleotide variants (sSNVs) in AD brains compared to age-matched controls. Molecular-barcoded deep (>1000X) gene panel sequencing of 311 prefrontal cortex samples showed enrichment of sSNVs and somatic insertions and deletions (sIndels) in cancer driver genes in AD brain compared to control, with recurrent, and often multiple, mutations in genes implicated in clonal hematopoiesis (CH) 8,9 . Pathogenic sSNVs were enriched in CSF1R+ microglia of AD brains, and the high proportion of microglia (up to 40%) carrying some sSNVs in cancer driver genes suggests mutation-driven microglial clonal expansion (MiCE). Analysis of single-nucleus RNA sequencing (snRNAseq) from temporal neocortex of 62 additional AD cases and controls exhibited nominally increased mosaic chromosomal alterations (mCAs) associated with CH 10,11 . Microglia carrying mCA showed upregulated pro-inflammatory genes, resembling the transcriptomic features of disease-associated microglia (DAM) in AD. Our results suggest that somatic driver mutations in microglia are common with normal aging but further enriched in AD brain, driving MiCE with inflammatory and DAM signatures. Our findings provide the first insights into microglial clonal dynamics in AD and identify potential new approaches to AD diagnosis and therapy.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Microglia in neurodegeneration
Hickman, S., Izzy, S., Sen, P., Morsett, L., & El Khoury, J. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0242-x · Cited by 1,710 · see citing works
Evolution and functional impact of rare coding variation from deep sequencing of human exomes
Tennessen, J. A., Bigham, A. W., O’Connor, T. D., Fu, W., Kenny, E. E., Gravel, S., McGee, S., Do, R., Liu, X., Jun, G., et al. (2012) · Science · doi:10.1126/science.1219240 · Cited by 1,613 · see citing works
The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers
Sondka, Z., Bamford, S., Cole, C. G., Ward, S. A., Dunham, I., & Forbes, S. A. (2018) · Nature Reviews Cancer · doi:10.1038/s41568-018-0060-1 · Cited by 1,597 · see citing works
Innate immune activation in neurodegenerative disease
Heneka, M. T., Kummer, M. P., & Latz, E. (2014) · Nature Reviews Immunology · doi:10.1038/nri3705 · Cited by 1,437 · see citing works
Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions
Mildner, A., Schmidt, H., Nitsche, M., Merkler, D., Hanisch, U.-K., Mack, M., Heikenwalder, M., Brück, W., Priller, J., & Prinz, M. (2007) · Nature Neuroscience · doi:10.1038/nn2015 · Cited by 1,089 · see citing works
Perry, V. H., Hume, D. A., & Gordon, S. (1985) · Neuroscience · doi:10.1016/0306-4522(85)90215-5 · Cited by 902 · see citing works
Microglia Heterogeneity in the Single-Cell Era
Masuda, T., Sankowski, R., Staszewski, O., & Prinz, M. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.01.010 · Cited by 784 · see citing works
Inherited causes of clonal haematopoiesis in 97,691 whole genomes
Bick, A. G., Weinstock, J. S., Nandakumar, S. K., Fulco, C. P., Bao, E. L., Zekavat, S. M., Szeto, M. D., Liao, X., Leventhal, M. J., Nasser, J., et al. (2020) · Nature · doi:10.1038/s41586-020-2819-2 · Cited by 733 · see citing works
Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease
Olah, M., Menon, V., Habib, N., Taga, M. F., Ma, Y., Yung, C. J., Cimpean, M., Khairallah, A., Coronas-Samano, G., Sankowski, R., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19737-2 · Cited by 722 · see citing works
Self-citationFriedman, B. A., Srinivasan, K., Ayalon, G., Meilandt, W. J., Lin, H., Huntley, M. A., Cao, Y., Lee, S.-H., Haddick, P. C. G., Ngu, H., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2017.12.066 · Cited by 662 · see citing works
MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road
Caunt, C. J., Sale, M. J., Smith, P. D., & Cook, S. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc4000 · Cited by 606 · see citing works
Macrophages at CNS interfaces: Ontogeny and function in health and disease
Kierdorf, K., Masuda, T., Jordão, M. J. C., & Prinz, M. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0201-x · Cited by 416 · cited 2× · see citing works
“Germline variants were removed by comparing against matched whole-genome or whole-exome sequencing data of the same individual.”
MethodSilvin, A., Uderhardt, S., Piot, C., Da Mesquita, S., Yang, K., Geirsdottir, L., Mulder, K., Eyal, D., Liu, Z., Bridlance, C., et al. (2022) · Immunity · doi:10.1016/j.immuni.2022.07.004 · Cited by 368 · see citing works
Microglia in Alzheimer's disease at single-cell level. Are there common patterns in humans and mice?
Chen, Y., & Colonna, M. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20202717 · Cited by 339 · see citing works
Marchetti, L., & Engelhardt, B. (2020) · Vascular Biology · doi:10.1530/vb-19-0033 · Cited by 304 · see citing works
Life histories of myeloproliferative neoplasms inferred from phylogenies
Williams, N., Lee, J., Mitchell, E., Moore, L., Baxter, E. J., Hewinson, J., Dawson, K. J., Menzies, A., Godfrey, A. L., Green, A. R., et al. (2022) · Nature · doi:10.1038/s41586-021-04312-6 · Cited by 285 · see citing works
Lund, H., Pieber, M., Parsa, R., Han, J., Grommisch, D., Ewing, E., Kular, L., Needhamsen, M., Espinosa, A., Nilsson, E., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07295-7 · Cited by 249 · see citing works
Somatic genomic changes in single Alzheimer’s disease neurons
Miller, M. B., Huang, A. Y., Kim, J., Zhou, Z., Kirkham, S. L., Maury, E. A., Ziegenfuss, J. S., Reed, H. C., Neil, J. E., Rento, L., et al. (2022) · Nature · doi:10.1038/s41586-022-04640-1 · Cited by 223 · see citing works
Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration
Ryu, J. K., Rafalski, V. A., Meyer-Franke, A., Adams, R. A., Poda, S. B., Rios Coronado, P. E., Pedersen, L. Ø., Menon, V., Baeten, K. M., Sikorski, S. L., et al. (2018) · Nature Immunology · doi:10.1038/s41590-018-0232-x · Cited by 213 · see citing works
Microglia in Brain Development, Homeostasis, and Neurodegeneration
Bohlen, C. J., Friedman, B. A., Dejanovic, B., & Sheng, M. (2019) · Annual Review of Genetics · doi:10.1146/annurev-genet-112618-043515 · Cited by 212 · see citing works
A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease
Mass, E., Jacome-Galarza, C. E., Blank, T., Lazarov, T., Durham, B. H., Ozkaya, N., Pastore, A., Schwabenland, M., Chung, Y. R., Rosenblum, M. K., et al. (2017) · Nature · doi:10.1038/nature23672 · Cited by 210 · cited 2× · see citing works
“4b) for the major brain 26 and blood 27 cell types ( HBA1 : red blood cell; CD3E : T-cell; CCR7 : B-cell; FCN1 : monocyte).”
Macroscopic somatic clonal expansion in morphologically normal human urothelium
Li, R., Du, Y., Chen, Z., Xu, D., Lin, T., Jin, S., Wang, G., Liu, Z., Lu, M., Chen, X., et al. (2020) · Science · doi:10.1126/science.aba7300 · Cited by 206 · see citing works
Clonal hematopoiesis is associated with protection from Alzheimer’s disease
Bouzid, H., Belk, J. A., Jan, M., Qi, Y., Sarnowski, C., Wirth, S., Ma, L., Chrostek, M. R., Ahmad, H., Nachun, D., et al. (2023) · Nature Medicine · doi:10.1038/s41591-023-02397-2 · Cited by 169 · see citing works
Park, J. S., Lee, J., Jung, E. S., Kim, M.-H., Kim, I. B., Son, H., Kim, S., Kim, S., Park, Y. M., Mook-Jung, I., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11000-7 · Cited by 155 · see citing works
High prevalence of focal and multi-focal somatic genetic variants in the human brain
Keogh, M. J., Wei, W., Aryaman, J., Walker, L., van den Ameele, J., Coxhead, J., Wilson, I., Bashton, M., Beck, J., West, J., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06331-w · Cited by 74 · cited 2× · see citing works
“Although gene panel sequencing of 20 AD brains 27 and whole exome sequencing of DNA from micro-dissected neuronal nuclei of 52 AD brains 28 found no consistent excess of clonal somatic mutations in AD, these studies were extremely limited in their ability to detect clonal somatic mutations by small…”
Genes, pathways and risk prediction in Alzheimer’s disease
Hardy, J., & Escott-Price, V. (2019) · Human Molecular Genetics · doi:10.1093/hmg/ddz163 · Cited by 27 · see citing works
Flagged first, then by citations
- Authors
- Huang, A. Y., Zhou, Z., Talukdar, M., Miller, M. B., Chhouk, B., Enyenihi, L., Rosen, I., Stronge, E., Zhao, B., Kim, D., Choi, J., Khoshkhoo, S., Kim, J., Ganz, J., Travaglini, K., Gabitto, M., Hodge, R., Kaplan, E., Lein, E., De Jager, P. L., Bennett, D. A., Lee, E. A., & Walsh, C. A.
- Affiliations
- Broad Institute (US)
- Boston Children's Hospital (US)
- Allen Institute for Brain Science (US)
- Rush University Medical Center (US)
- Corresponding author
- Lee, Eunjung Alice
- Walsh, Christopher A.
- ORCID
- Huang, August Yue
- Zhou, Zinan
- Talukdar, Maya
- Miller, Michael B.
- Chhouk, Brian
- Enyenihi, Liz
- Zhao, Boxun
- Kim, Dachan
- Choi, Jaejoon
- Khoshkhoo, Sattar
- Kim, Junho
- Ganz, Javier
- Travaglini, Kyle
- Gabitto, Mariano
- Hodge, Rebecca
- Kaplan, Eitan
- Lein, Ed
- De Jager, Philip L.
- Bennett, David A.
- Lee, Eunjung Alice
- Walsh, Christopher A.
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2024-01-04
- PMC
- PMC10802273
- OpenAlex
- W4390656930
- Cited by
- 16
- References
- 26
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 3
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (1r01ag088082-01)
- Manton Center for Orphan Disease Research, Boston Children's Hospital
- National Institute on Aging (R01AG017917, K08AG065502, DP2AG072437, U01AG046152, R01AG015819, P30AG010161, U01AG061356, R56AG079857, DP2AG086138, R01AG078929, R01AG070921, R01AG082346, P30AG072975, U19AG060909)
- National Heart, Lung, and Blood Institute (T32HL007627)
- National Institute of General Medical Sciences (T32GM007753, T32GM144273)
- National Institute of Neurological Disorders and Stroke (R01NS032457, K08NS128272, R25NS065743)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD105351)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- Alzheimer's disease, somatic mutations, microglia, cancer driver genes, clonal hematopoiesis, disease-associated microglia, neuroinflammation, mosaic chromosomal alterations, CSF1R, prefrontal cortex, temporal neocortex, single-nucleus RNA sequencing, single nucleotide variants
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
