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Cited by 115Alzheimer's disease research and treatmentsSingle-cell and spatial transcriptomicsDementia and Cognitive Impairment Research

Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer’s disease

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Miyoshi, Emily, Morabito, Samuel, Henningfield, Caden M., Das, Sudeshna, Rahimzadeh, Negin, Shabestari, Sepideh Kiani, Michael, Neethu, Emerson, Nora +19 more·2024·Nature Genetics
DOI 10.1038/s41588-024-01961-xPMC PMC11631771

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Abstract

The pathogenesis of Alzheimer's disease (AD) depends on environmental and heritable factors, with remarkable differences evident between individuals at the molecular level. Here we present a transcriptomic survey of AD using spatial transcriptomics (ST) and single-nucleus RNA-seq in cortical samples from early-stage AD, late-stage AD, and AD in Down Syndrome (AD in DS) donors. Studying AD in DS provides an opportunity to enhance our understanding of the AD transcriptome, potentially bridging the gap between genetic mouse models and sporadic AD. Our analysis revealed spatial and cell-type specific changes in disease, with broad similarities in these changes between sAD and AD in DS. We performed additional ST experiments in a disease timecourse of 5xFAD and wildtype mice to facilitate cross-species comparisons. Finally, amyloid plaque and fibril imaging in the same tissue samples used for ST enabled us to directly link changes in gene expression with accumulation and spread of pathology.

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  • Different pathological features may generate distinct glial niches, including plaque-associated microglial and astrocytic responses.

    “Recent spatial and single-nucleus studies have emphasized that different pathological features may generate distinct glial niches, including plaque-associated microglial and astrocytic responses [57,58].”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [57]

    The Results sections on conformation-specific amyloid signatures and imaging mass cytometry report distinct plaque- and fibril-associated gene signatures, as well as changes in microglia and astrocytes in Alzheimer’s disease (page unavailable). They do not establish that different pathological features generate distinct glial niches or directly identify both glial responses as plaque-associated. (LLM, conf=0.81)

    Experimental — accuracy not yet measured

  • Recent transcriptomic studies have demonstrated changes in the inhibitory-to-excitatory neuronal ratio and microglial cell states in the brain of people with DS.

    “Recent transcriptomic studies have begun to address this by systematically interrogating how the extra copy of Hsa21 alters transcript expression within the brain of people with DS, demonstrating changes in the inhibitory-to-excitatory neuronal ratio, and microglial cell states [49, 51].”

    From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [49]

    The Results section (“ST and cellular transcriptomics of AD”; page not provided) reports shifts in cell-state composition, especially among microglia, in samples from people with Down syndrome and Alzheimer’s disease (DSAD). It identifies excitatory and inhibitory neurons but does not report a change in their ratio. The study also examined DSAD, not Down syndrome without Alzheimer’s disease. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Re-analysis of a previously published snRNAseq dataset showed upregulated expression of APOE in astrocytes in DSAD compared to healthy controls.

    “In support of these data, re-analysis of a previously published snRNAseq dataset showed the upregulated expression of APOE in astrocytes in DSAD compared to healthy controls [49].”

    From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [49]

    The Methods (Differential gene expression analysis; page unavailable) report a DSAD-versus-control snRNA-seq comparison, but say it used a dataset generated in this study; the re-analysis of previously published datasets compared late-stage AD with controls. No passage found reports APOE upregulation in DSAD astrocytes (searched: APOE and APOE astrocytes DSAD). (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • APP transcription is elevated in many cell types in the brains of people with DSAD, including cell types in which APOE expression is also raised.

    “Consistent with previous reports [49, 51], we observe that APP transcription is elevated in many cell types in the brains of people with DSAD, including cell types in which we find APOE expression is also raised.”

    From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [49]

    The Results section, “Regional and cell-type-specific gene expression changes” (page unavailable), reports that APP is upregulated in DSAD samples, while noting that its expression is not significantly different from controls in one spatial cluster. It does not establish that APP is elevated in many cell types specifically. The APOE finding is phrased as the citing authors’ own observation, not as a finding attributed to this source. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Cited by

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Authors
Miyoshi, E., Morabito, S., Henningfield, C. M., Das, S., Rahimzadeh, N., Shabestari, S. K., Michael, N., Emerson, N., Reese, F., Shi, Z., Cao, Z., Srinivasan, S. S., Scarfone, V. M., Arreola, M. A., Lu, J., Wright, S., Silva, J., Leavy, K., Lott, I. T., Doran, E., Yong, W. H., Shahin, S., Perez-Rosendahl, M., Alzheimer’s Biomarkers Consortium–Down Syndrome (ABC–DS), Head, E., Green, K. N., & Swarup, V.
Affiliations
University of California, Irvine (US)
Corresponding author
Swarup, Vivek
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2024-11-22
Volume
56
Issue
12
Pages
2704-2717
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-024-01961-x
PMC
PMC11631771
OpenAlex
W4404613107
Cited by
115
References
37
Citations by year
2026: 52 · 2025: 52 · 2024: 10 · 2022: 1
FWCI
32.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • National Institutes of Health (UL1TR001414, 5f31ag076308-02, UL1TR001873, UL1TR001857, UL1TR002373, UL1TR002345)
  • National Institute on Aging (F31 AG076308, P50AG005133, U01AG051406, U01AG051412, P50AG008702, P50AG005681, RF1AG071683, R01AG071683, U19AG068054, P30AG066444, T32AG000096, U54AG054349, P30AG062715, U24AG021886, P30AG062421, P30AG066519)
  • National Institute on Drug Abuse (U01DA053826)
  • National Institute of General Medical Sciences (T32GM136624)
  • National Institute of Neurological Disorders and Stroke (P01NS084974, R01NS135556)
  • National Center for Advancing Translational Sciences
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090256, U54HD087011, P50HD105353)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, spatial transcriptomics, single-nucleus transcriptomics, cortical layers, glial inflammation, amyloid, genetic risk, intercellular communication, cross-species transcriptomics, sporadic Alzheimer's disease

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