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Magnetic resonance microscopy maps widespread effects of Alzheimer’s disease on brain structures and behavior in mice

Nature Neuroscience (2026)Cite this article

Subjects

Abstract

Alzheimer’s disease has widespread effects on brain structure, function and behavior, but we lack a systematic dissection of its impact across hundreds of forebrain and brainstem regions. Here, using diffusion tensor MRI at 25 µm, we mapped the global consequences of mutations in APP and PSEN1 across 231 regions of interest (ROIs) in male and female 5×FAD BXD hybrid mice at 14 months. Over half of the ROIs change in volume along rostrocaudal and mediolateral axes of the CNS, with unexpected swelling in the neocortex, hippocampus and amygdala of up to 10%, counterbalanced by shrinkage in the thalamus, brainstem and most white matter tracts. Yet, total brain volume is unaltered. Variation in individual ROI volumes is highest in females. Differences in fear acquisition and contextual memory performance covary with volumes of several regions and can have opposite polarities between cases and controls. These structural benchmarks establish a foundation for testing therapeutic interventions in preclinical trials.

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Fig. 1: Workflow to evaluate the impact of 5×FAD transgene effects on volumes of 231 brain regions.
Fig. 2: Spatial and contrast resolution increase precision in structure delineation.
Fig. 3: High-resolution DTI reveals many effects of the 5×FAD transgene on ROI volumes.
Fig. 4: The 5×FAD transgene causes many significant changes in the fractional volume of brain regions.
Fig. 5: Sex differences of fractional volumes in cases and controls.
Fig. 6: LSM data on Aβ levels, ROI volumes and NeuN+ cell numbers in AD-BXD77 F1 mice, the most severely affected genetic background.
Fig. 7: Volume changes in specific ROIs are linked to behavioral performance.

Data availability

All ROI volumetric data and metadata (for example, left and right ROI volumes and bilateral sums) are available at genenetwork.org (see Methods for details). All image data and metadata sets are available at civmimagespace.civm.duhs.duke.edu/.

Code availability

Image acquisition, reconstruction and postprocessing was accomplished using a series of imaging pipelines summarized in Supplementary Fig. 12 of Johnson et al.24. Descriptions of these pipelines have been published previously with the references included in the table below.

Code

Reference

Version

Link

Reconstruction

87

v0.7.00-536-g6be1997

https://github.com/mrirecon/bart

DSI Studio

101

2022-12

https://dsi-studio.labsolver.org/

Registration

102

2024

https://github.com/andersonion/SAMBA

LSM Registration

22

2023

https://github.com/CIVM-DIIL/MRH_LSM_registration

Cell counting

23

2023

https://github.com/CIVM-DIIL/NeuronCounting

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Acknowledgements

We thank M. McCarty, C. Bohl and L. Lu for help in generating BXD and AD-BXD F1 progeny and colony management. We thank G. D. Rosen for contributions to the production of the rCCFv3 delineations used in this study, R. Azrak and H. Mansour for technical assistance in image processing and D. Arends for help in statistical design. This work is supported by NIH R01 AG070913 (R.W.W. and G.A.J.), NIH R01AG057914 (C.C.K.), North Carolina Biotechnology Center Grant 2021-IIG-2101 (G.A.J.) and NIH/NINDS R01NS120954 (G.A.J.). Support for mouse aging and AD model colonies is provided in part by the UTHSC Center for Integrative and Translational Genomic (R.W.W. and D.G.A.) and the UT-ORNL Governor’s Chair (R.W.W.).

Author information

Author notes

  1. These authors contributed equally: Yuqi Tian, Kathryn Hornburg.

  2. These authors jointly supervised this work: David G. Ashbrook, G. Allan Johnson, Robert W. Williams.

Authors and Affiliations

  1. Center for In Vivo Microscopy, Department of Radiology, Duke University Medical Center, Durham, NC, USA

    Yuqi Tian, Kathryn Hornburg, Wyatt Austin, James J. Cook, Yi Qi & G. Allan Johnson

  2. Department of Neurology, Duke University Medical Center, Durham, NC, USA

    Leonard E. White

  3. Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA

    John T. Killmar, David G. Ashbrook & Robert W. Williams

  4. Department of Neurology, University of Michigan, Ann Arbor, MI, USA

    Catherine C. Kaczorowski

  5. Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, UK

    David G. Ashbrook

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The following authors contributed to each of the roles that follow in alphabetical order. Conceptualization: D.G.A., G.A.J. and R.W.W. Methodology: D.G.A., W.A., J.J.C., G.A.J., C.C.K., J.T.K., K.H., Y.Q., Y.T. and R.W.W. Software: J.J.C., K.H., W.A. and Y.T. Validation: D.G.A., J.J.C., K.H., G.A.J. and R.W.W. Formal analysis: D.G.A., J.J.C., K.H., L.E.W., G.A.J. and R.W.W. Investigation: K.H., J.J.C., Y.T., L.E.W., D.G.A., G.A.J. and R.W.W. Resources: W.A., J.J.C., Y.Q., J.T.K., C.C.K., D.G.A., G.A.J. and R.W.W. Data curation: D.G.A., J.J.C., K.H., G.A.J., Y.Q., Y.T., L.E.W. and R.W.W. Writing, original draft: D.G.A., K.H., G.A.J. and R.W.W. Writing, reviewing and editing: D.G.A., J.J.C., K.H., G.A.J., C.C.K., Y.T., L.E.W. and R.W.W. Visualization: D.G.A., J.J.C., K.H., G.A.J., Y.T. and R.W.W. Supervision: D.G.A., G.A.J. and R.W.W. Project administration: D.G.A., G.A.J. and R.W.W. Funding acquisition: D.G.A., C.C.K., G.A.J. and R.W.W. All the authors contributed to the article and approved the submitted version.

Corresponding authors

Correspondence to David G. Ashbrook, G. Allan Johnson or Robert W. Williams.

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Nature Neuroscience thanks Todd Golde, Noam Shemesh 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 Percentage volume changes of ROIs caused by the 5×FAD transgene at four dorsoventral levels.

Volume changes range from 10% increases (more intense reds) to 10% decreases (more intense blues). We provide four schematic horizontal sections—a through d—at different dorsoventral (DV) levels, from dorsal-most to ventral-most. The ontology of all ROIs is given in Fig. 4a with significance levels of change. A subset of ROIs are marked in the four panels with acronym labels as in Fig. 3a, and with definitions as given in Fig. 4e and Supplementary Tables.

Extended Data Fig. 2 3D images highlighting eight ROIs in which fractional anisotropy decreased in the 5×FAD cases compared to controls by 10 to 17% compared to controls.

The gray scale MRH 3D volumes are taken from the DMBA. a,b, Ventral and dorsal perspectives of the entire mouse brain as imaged using the axial diffusivity (AD) scalar metric, one of multiple aligned DTI maps used to delineate ROIs. Major fiber tracts, ventricles and blood vessels are easily resolved. The DMBA coordinate space is a consensus for the C57BL/6J strain at stereotaxic precision. The bregma point is at the intersection of the horizontal white line and the mid-sagittal plane. c,d, Similar images of lateral perspective from right and left sides that clearly define the dorsoventral positions of the eight ROIs. Images were rendered in Imaris v10.2. Abbreviations: ACC: anterior cingulate cortex; BLA: basolateral amygdala, cst: corticospinal tract (defined to include almost all fibers in the pyramids); EPF: endopiriform nucleus; HGN: hypoglossal nucleus; LSN: lateral septal nucleus; mel: medial lemniscus; SUT: subthalamic nucleus. The specific values in this figure are based on AD-BXD77 F1 data and are given in tabular format in Fig. 6i.

Supplementary information

Reporting Summary

Supplementary Tables 1–10

Recent MRI studies and data and metadata related to Figs. 3–7.

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Tian, Y., Hornburg, K., Austin, W. et al. Magnetic resonance microscopy maps widespread effects of Alzheimer’s disease on brain structures and behavior in mice. Nat Neurosci (2026). https://doi.org/10.1038/s41593-025-02199-4

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