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Reply to: a quantitative trait locus for reduced microglial APOE expression associates with reduced cerebral amyloid angiopathy

Nature Genetics (2026)Cite this article

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The Original Article was published on 26 January 2026

arising from Shade LMP et al. Nature Genetics https://doi.org/10.1038/s41588-024-01939-9 (2024).

Identifying the mechanistic pathways that drive associations between genetic variants and disease phenotypes is a foundational challenge in complex disease genomics. Among the previously unreported associations discovered in our recent genome-wide association study (GWAS) of dementia-associated neuropathology endophenotypes (NPEs), we identified a locus near APOE associated with cerebral amyloid angiopathy (CAA), independent of APOE ε diplotypes1. Using bulk RNA-seq sampled from the neocortex and methylation data from the Religious Orders Study and the Memory and Aging Project (ROSMAP), we further identified statistical colocalization2 between CAA, APOC2 expression and several CpG methylation sites proximal to APOC2. Based on these results, we hypothesized that APOC2 may be the target gene of this genetic signal for CAA risk despite its proximity to the well-known dementia and CAA risk gene, APOE3.

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Data availability

The gene expression data and the clinical phenotyping are available from the SEA-AD study website via the AD Knowledge Portal (accession syn26223298, https://www.synapse.org/Synapse:syn26223298). The SEA-AD whole-genome sequencing data is available from the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (https://dss.niagads.org/studies/sa000065/). ROSMAP data can be requested at https://www.radc.rush.edu and https://www.synapse.org. ADGC data can be requested from NIAGADS at https://www.niagads.org/resources/related-projects/alzheimers-disease-genetics-consortium-adgc-collection. NACC neuropathology data can be requested at https://naccdata.org/.

Code availability

This study did not use any custom code or software.

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Author information

Authors and Affiliations

  1. Department of Biostatistics, University of Kentucky College of Public Health, Lexington, KY, USA

    Lincoln M. P. Shade, Qi Qiao, Yuriko Katsumata & David W. Fardo

  2. Sanders-Brown Center on Aging and Alzheimer’s Disease Research Center, University of Kentucky, Lexington, KY, USA

    Qi Qiao, Yuriko Katsumata, Lance A. Johnson, Mark T. W. Ebbert, Peter T. Nelson & David W. Fardo

  3. Department of Medicine, University of Washington, Seattle, WA, USA

    Shubhabrata Mukherjee

  4. Division of General Internal Medicine, University of Washington, Seattle, WA, USA

    Jai G. Broome

  5. Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA

    Lance A. Johnson

  6. Department of Neuroscience, University of Kentucky College of Medicine, Lexington, KY, USA

    Mark T. W. Ebbert

  7. Division of Biomedical Informatics, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, KY, USA

    Mark T. W. Ebbert & David W. Fardo

  8. Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY, USA

    Peter T. Nelson

Authors
  1. Lincoln M. P. Shade
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  2. Qi Qiao
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  3. Yuriko Katsumata
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  4. Shubhabrata Mukherjee
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  5. Jai G. Broome
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  6. Lance A. Johnson
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  7. Mark T. W. Ebbert
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  8. Peter T. Nelson
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  9. David W. Fardo
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Contributions

L.M.P.S. and D.W.F. conceptualized the response, designed the analyses, initiated some analyses and drafted the manuscript. Q.Q. prepared the data and performed the analyses. Y.K., S.M., J.G.B., L.A.J., M.T.W.E. and P.T.N. critically reviewed the manuscript and contributed to the interpretation of the results.

Corresponding author

Correspondence to David W. Fardo.

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All authors declare no competing interests.

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Nature Genetics thanks Timothy Chang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Shade, L.M.P., Qiao, Q., Katsumata, Y. et al. Reply to: a quantitative trait locus for reduced microglial APOE expression associates with reduced cerebral amyloid angiopathy. Nat Genet (2026). https://doi.org/10.1038/s41588-025-02473-y

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