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A quantitative trait locus for reduced microglial APOE expression associates with reduced cerebral amyloid angiopathy

Nature Genetics volume 58, pages 271–272 (2026)Cite this article

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Matters Arising to this article was published on 26 January 2026

The Original Article was published on 08 October 2024

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

The apolipoprotein E (APOE) ε4 and ε2 alleles are, respectively, the most risk increasing and risk decreasing, common genetic risk factors for Alzheimer’s disease (AD)1, strongly affecting Aβ burden in the brain parenchyma and also at the level of the brain vasculature, that is cerebral amyloid angiopathy (CAA)1,2, which relates to increased risk for amyloid-related imaging abnormalities (ARIA) in APOE ε4 carriers receiving anti-Aβ antibody treatments3. Ref. 4 reports the largest-to-date genome-wide association study (GWAS) of neuropathological traits, identifying a variant protective of CAA in the APOE locus, independent of APOE ε4 and ε2, with downstream analyses implicating the nearby APOC2 gene—but not APOE—through local effects on methylation in brain tissue. Here we provide evidence that their genetic signal for reduced CAA also relates to an effect on reduced microglial APOE expression and sheds additional light on its association with CAA and AD risk. These new insights are concordant with converging rodent work and initial human studies that support decreasing APOE (particularly APOE ε4) levels is protective for AD5,6,7,8,9, further heralding APOE reduction as a promising therapeutic avenue for both AD and CAA.

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Data availability

Data used in the CAA and AD risk analyses are available upon application to: dbGaP (https://www.ncbi.nlm.nih.gov/gap/), NIAGADS (https://www.niagads.org/), LONI (https://ida.loni.usc.edu/), AMP-AD knowledge portal/Synapse (https://www.synapse.org/), Rush (https://www.radc.rush.edu/), NACC (https://naccdata.org/), UKB (https://www.ukbiobank.ac.uk/) and MCSA (https://www.mayo.edu/research/centers-programs/alzheimers-disease-research-center/data-requests). The specific data repositories and identifiers for ADGC and ADSP data are indicated in Supplementary Table 1. Microglia eQTL datasets are available from: ref. 10—AMP-AD knowledge portal/Synapse (https://www.synapse.org/; identifier: syn52335732); ref. 11—AMP-AD knowledge portal/Synapse (https://www.synapse.org/; identifier: syn26207321).

Code availability

All presented analyses made use of standard functionalities available in R v4.2.1 (libraries: ‘plor’, ‘coloc’ and ‘locuscomparer’) and BOLT-LMM v2.3.6. Codes are available at https://github.com/Belloy-Lab/APOE_microglia_CAA. Processing of genetic and phenotypic data is described in refs. 13,14.

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Acknowledgements

This study was funded by the NIH (R00AG075238 to M.E.B., AG060747 and AG047366 to M.D.G. and AG006786 to J.G.-R.). Data for this study were prepared, archived and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site at the University of Pennsylvania (U24-AG041689), funded by the National Institute on Aging. The contents of this study do not represent the views of the National Institutes of Health, the U.S. Department of Veterans Affairs or the United States Government. Additional data-specific acknowledgements are provided in the Supplementary Note.

Author information

Authors and Affiliations

  1. NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA

    Michael E. Belloy

  2. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA

    Michael E. Belloy

  3. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Michael E. Belloy & Michael D. Greicius

  4. Departments of Neurology, Mayo Clinic, Rochester, MN, USA

    Jonathan Graff-Radford

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  1. Michael E. Belloy
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  2. Jonathan Graff-Radford
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Contributions

M.E.B. and M.D.G. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. M.E.B. performed data acquisition and analyses, designed analyses and study, wrote paper and obtained funding. J.G.-R. was involved in data, funding and resource acquisition. M.D.G. designed the study and analyses, supervised work and obtained funding. All authors contributed to the critical revision of the manuscript.

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Correspondence to Michael E. Belloy.

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The 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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Extended data

Extended Data Fig. 1 The rs2288911 and rs7247551 variants are microglial expression quantitative trait loci for APOE, not APOC2.

The locus comparison (left) and locus zoom (right) plots indicate that the two SNPs are microglia eQTLs for APOE and APOC2 in two independent datasets: (a) ref. 10 (n = 424) and (b) ref. 11 (n = 400). Color coding of variants/dots indicates LD (R2) with rs2288911, marked by purple diamonds. rs2288911 was identified in ref. 10 as the lead microglia-specific eQTL for APOE and is in strong LD with rs7247551 identified by ref. 4 (R2 = 0.98), who related its effect to APOC2 and local methylation. rs2288911 shows only a nominal association with microglial APOC2 expression in (a) and none in (b), indicating it is not an eQTL for APOC2. Conversely, it is strongly associated with APOE expression in both datasets with consistent beta coefficients that suggest close to 30% reduced microglia APOE expression for a single T allele. eQTL, expression quantitative trait locus; LD, linkage disequilibrium; PP4, colocalization poster probability for hypothesis 4: association with both traits and a shared variant.

Extended Data Table 1 Association of rs2288911*T with cerebral amyloid angiopathy and Alzheimer’s disease
Full size table

Supplementary information

Supplementary Information (download PDF )

Supplementary Figs. 1 and 2, Supplementary Table 1 and Supplementary Note (data acknowledgements).

Reporting Summary (download PDF )

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Belloy, M.E., Graff-Radford, J. & Greicius, M.D. A quantitative trait locus for reduced microglial APOE expression associates with reduced cerebral amyloid angiopathy. Nat Genet 58, 271–272 (2026). https://doi.org/10.1038/s41588-025-02472-z

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