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Peer-reviewedCC BY-NC-NDActa neuropathologica

Tau A152T risk variant drives distinct cell type transcriptional signatures in AD and PSP.

  • Meredith T Lilley1,2
  • Yingxue Ren3
  • Disha Soni4,5
  • Emily C Sanborn4,5
  • Jordan D Marks1,6
  • Yunfei Chen4,5
  • Yan Yan7,8
  • Michael DeTure2
  • Bailey Rawlinson2
  • Dennis W Dickson1,2
  • Casey N Cook9,10,11,12
12 affiliations
  1. 1Neuroscience Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
  2. 2Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
  3. 3Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA.
  4. 4Department of Molecular Medicine, University of South Florida, Tampa, FL, USA.
  5. 5Byrd Alzheimer's Center and Research Institute, University of South Florida, Tampa, FL, USA.
  6. 6Medical Scientist Training Program, Mayo Clinic Alix School of Medicine, Rochester, MN, USA.
  7. 7Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA.
  8. 8Department of Internal Medicine, Adventhealth Sebring, Sebring, FL, USA.
  9. 9Neuroscience Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Jacksonville, FL, USA. [email protected].
  10. 10Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. [email protected].
  11. 11Department of Molecular Medicine, University of South Florida, Tampa, FL, USA. [email protected].
  12. 12Byrd Alzheimer's Center and Research Institute, University of South Florida, Tampa, FL, USA. [email protected].
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Abstract

The A152T point mutation is a rare genetic variant in the tau gene (MAPT) that is linked to risk of Alzheimer's disease (AD) and frontotemporal dementia spectrum disorders, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). To uncover mechanisms through which the A152T variant contributes to risk of tauopathy, we performed single-nucleus RNA sequencing (snRNA-seq) on postmortem brain tissue collected from A152T carriers and pathology-matched non-carriers with either AD or PSP, along with age-matched controls. These efforts revealed that despite similar cell type composition across groups, A152T carriers exhibited distinct cell type-specific transcriptional changes in both AD and PSP. Differential expression analysis identified excitatory neurons, oligodendrocytes, and astrocytes as the most affected cell populations in AD and PSP, and these same cell types showed the strongest A152T-specific changes. These findings identify transcriptional alterations that differentiate sporadic AD and sporadic PSP from AD-A152T and PSP-A152T, as well as shared molecular signatures unique to A152T carriers in both PSP and AD. Donor-level pseudo-bulk analyses showed broad directional support with the single-nucleus findings although the proportion of donor-supported genes varied across cell type and comparison. Importantly, merging sporadic and A152T cases into a single disease group was found to mask transcriptional differences in several cell types in both AD and PSP, indicating divergence in transcriptional signature and highlighting the importance of screening for genetic risk variants like A152T in snRNA-seq data from human cohorts.

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Cite

BibTeXRIS
BibTeX
@article{lilley2026a152t,
  title = {{Tau A152T risk variant drives distinct cell type transcriptional signatures in AD and PSP.}},
  author = {Meredith T Lilley and Yingxue Ren and Disha Soni and Emily C Sanborn and Jordan D Marks and Yunfei Chen and Yan Yan and Michael DeTure and Bailey Rawlinson and Dennis W Dickson and Casey N Cook},
  journal = {Acta neuropathologica},
  year = {2026},
  month = oct,
  doi = {10.1007/s00401-026-03110-6},
  url = {https://europepmc.org/article/MED/42909646},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Tau A152T risk variant drives distinct cell type transcriptional signatures in AD and PSP.
AU  - Meredith T Lilley
AU  - Yingxue Ren
AU  - Disha Soni
AU  - Emily C Sanborn
AU  - Jordan D Marks
AU  - Yunfei Chen
AU  - Yan Yan
AU  - Michael DeTure
AU  - Bailey Rawlinson
AU  - Dennis W Dickson
AU  - Casey N Cook
PY  - 2026
DA  - 2026/10/23
JO  - Acta neuropathologica
DO  - 10.1007/s00401-026-03110-6
UR  - https://europepmc.org/article/MED/42909646
AB  - The A152T point mutation is a rare genetic variant in the tau gene (MAPT) that is linked to risk of Alzheimer's disease (AD) and frontotemporal dementia spectrum disorders, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). To uncover mechanisms through which the A152T variant contributes to risk of tauopathy, we performed single-nucleus RNA sequencing (snRNA-seq) on postmortem brain tissue collected from A152T carriers and pathology-matched non-carriers with either AD or PSP, along with age-matched controls. These efforts revealed that despite similar cell type composition across groups, A152T carriers exhibited distinct cell type-specific transcriptional changes in both AD and PSP. Differential expression analysis identified excitatory neurons, oligodendrocytes, and astrocytes as the most affected cell populations in AD and PSP, and these same cell types showed the strongest A152T-specific changes. These findings identify transcriptional alterations that differentiate sporadic AD and sporadic PSP from AD-A152T and PSP-A152T, as well as shared molecular signatures unique to A152T carriers in both PSP and AD. Donor-level pseudo-bulk analyses showed broad directional support with the single-nucleus findings although the proportion of donor-supported genes varied across cell type and comparison. Importantly, merging sporadic and A152T cases into a single disease group was found to mask transcriptional differences in several cell types in both AD and PSP, indicating divergence in transcriptional signature and highlighting the importance of screening for genetic risk variants like A152T in snRNA-seq data from human cohorts.
SN  - 0001-6322
SN  - 1432-0533
ER  -