Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations

Nordbeck AJ, Martá-Ariza M, Ek Olofsson H, Kanshin E, Ueberheide B, Jones K, Sanford B, Hamlett ED, Head E, Mufson EJ, Perez SE, …, Granholm AC · 2026 · Alzheimer's & Dementia · Atlas ID NOR2026

What this study shows

Spatial transcriptomics plus localized proteomics on human post-mortem hippocampus show that mTOR pathway signalling is significantly altered in specific hippocampal subfields in Down syndrome with Alzheimer's disease neuropathology, while insulin pathway signalling is altered specifically in dentate granule neurons — pointing to subregion- and cell-type-specific mTOR/insulin dysregulation rather than a uniform whole-tissue shift. Explicitly framed by the authors as preliminary.

Abstract

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Down syndrome (DS) is caused by a complete or partial trisomy of chromosome 21, resulting in variable intellectual disabilities and a high risk for early-onset Alzheimer's disease (DS-AD). Dysregulation of the mammalian target of rapamycin (mTOR) and insulin (INS) signaling pathways has been reported in DS. We hypothesized that upstream alterations in these two pathways contribute to hippocampal dysfunction in DS-AD.

Read the full abstract on PubMed →

At a glance

Evidence type	M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Human post-mortem hippocampus (Down syndrome with AD neuropathology vs neurotypical controls)) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is.
Study type	5 - Mechanistic / In Vitro
Model system	Human post-mortem hippocampus (Down syndrome with AD neuropathology vs neurotypical controls)
Journal	Alzheimer's & Dementia
Year	2026
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1002/alz.71776 · PMID 42635110 · Free full text (PMC13501503)

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	none (observational post-mortem comparison)
Target	mTOR and insulin signalling pathways across hippocampal subfields
Model	human post-mortem hippocampus (Down syndrome with Alzheimer's neuropathology versus age-matched neurotypical controls)
Effect	mTOR pathway signalling differed in specific hippocampal subfields and insulin pathway signalling in dentate granule neurons, reported by the authors as preliminary.

In the Atlas

Cite this paper

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Nordbeck, A. J., Martá-Ariza, M., Ek Olofsson, H., Kanshin, E., Ueberheide, B., Jones, K., Sanford, B., Hamlett, E. D., Head, E., Mufson, E. J., Perez, S. E., Wisniewski, T., Guzman, S., & Granholm, A. C. (2026). Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations. Alzheimer's & Dementia. https://doi.org/10.1002/alz.71776

@article{NOR2026,
  author       = {Nordbeck, A. J. and Martá-Ariza, M. and Ek Olofsson, H. and Kanshin, E. and Ueberheide, B. and Jones, K. and Sanford, B. and Hamlett, E. D. and Head, E. and Mufson, E. J. and Perez, S. E. and Wisniewski, T. and Guzman, S. and Granholm, A. C.},
  title        = {{Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations}},
  journal      = {Alzheimer's & Dementia},
  year         = {2026},
  doi          = {10.1002/alz.71776},
  note         = {PMID: 42635110},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record NOR2026) [Data set]. https://mtor-atlas.org/study/NOR2026/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_NOR2026,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record NOR2026},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/NOR2026/},
  doi          = {10.5281/zenodo.22059963}
}

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