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Peer-reviewedCC BY-NCJournal of Alzheimer s Disease

Single-cell transcriptomic atlas of Alzheimer's disease middle temporal gyrus reveals region, cell type, and sex specificity of gene expression with novel genetic risk for MERTK in female

  • Le Zhang1,2
  • Tianyu Liu3,4,1
  • Chuan H. He1
  • Anthony Russo1,5
  • Sarah Coffey1,2
  • Dominic Yin1,3
  • I-Uen Yvonne Hsu2,3
  • Chi Zhang3
  • Yixuan Ye3,6,1,2
  • Chang Su3,6,1,2
  • Joshua M. Spurrier6,1,2,7,8
  • LaShae Nicholson6,1,2,8
11 more authors
  • Brian W. Kunkle9,6,10
  • Eden R. Martin9,7,1
  • Omar G. Rodriguez9,3
  • Lissette Gomez9,6,1,2
  • Rui B. Chang2
  • Carla Vanina Rothlin7,8
  • Sourav Ghosh1,8
  • Pallavi P. Gopal6,10
  • David A. Hafler7,1
  • Hongyu Zhao3
  • Stephen M. Strittmatter6,1,2
10 affiliations
  1. 1Department of Neurology, Yale University School of Medicine, New Haven, CT, USA
  2. 2Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA
  3. 3Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA
  4. 4Yale University
  5. 5Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, USA
  6. 6Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, CT, USA
  7. 7Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
  8. 8Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA
  9. 9University of Miami
  10. 10Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
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Abstract

Alzheimer’s disease, the most common age-related neurodegenerative disease, is closely associated with both amyloid-ß plaque and neuroinflammation. Two thirds of Alzheimer’s disease patients are females and they have a higher disease risk. Moreover, women with Alzheimer’s disease have more extensive brain histological changes than men along with more severe cognitive symptoms and neurodegeneration. To identify how sex difference induces structural brain changes, we performed unbiased massively parallel single nucleus RNA sequencing on Alzheimer’s disease and control brains focusing on the middle temporal gyrus, a brain region strongly affected by the disease but not previously studied with these methods. We identified a subpopulation of selectively vulnerable layer 2/3 excitatory neurons that that were RORB-negative and CDH9-expressing. This vulnerability differs from that reported for other brain regions, but there was no detectable difference between male and female patterns in middle temporal gyrus samples. Disease-associated, but sex-independent, reactive astrocyte signatures were also present. In clear contrast, the microglia signatures of diseased brains differed between males and females. Combining single cell transcriptomic data with results from genome-wide association studies (GWAS), we identified MERTK genetic variation as a risk factor for Alzheimer’s disease selectively in females. Taken together, our single cell dataset revealed a unique cellular-level view of sex-specific transcriptional changes in Alzheimer’s disease, illuminating GWAS identification of sex-specific Alzheimer’s risk genes. These data serve as a rich resource for interrogation of the molecular and cellular basis of Alzheimer’s disease.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026singlecell,
  title = {{Single-cell transcriptomic atlas of Alzheimer's disease middle temporal gyrus reveals region, cell type, and sex specificity of gene expression with novel genetic risk for MERTK in female}},
  author = {Le Zhang and Tianyu Liu and Chuan H. He and Anthony Russo and Sarah Coffey and Dominic Yin and I-Uen Yvonne Hsu and Chi Zhang and Yixuan Ye and Chang Su and Joshua M. Spurrier and LaShae Nicholson and Brian W. Kunkle and Eden R. Martin and Omar G. Rodriguez and Lissette Gomez and Rui B. Chang and Carla Vanina Rothlin and Sourav Ghosh and Pallavi P. Gopal and David A. Hafler and Hongyu Zhao and Stephen M. Strittmatter},
  journal = {Journal of Alzheimer s Disease},
  year = {2026},
  month = sep,
  doi = {10.1177/13872877261480719},
  url = {https://doi.org/10.1177/13872877261480719},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Single-cell transcriptomic atlas of Alzheimer's disease middle temporal gyrus reveals region, cell type, and sex specificity of gene expression with novel genetic risk for MERTK in female
AU  - Le Zhang
AU  - Tianyu Liu
AU  - Chuan H. He
AU  - Anthony Russo
AU  - Sarah Coffey
AU  - Dominic Yin
AU  - I-Uen Yvonne Hsu
AU  - Chi Zhang
AU  - Yixuan Ye
AU  - Chang Su
AU  - Joshua M. Spurrier
AU  - LaShae Nicholson
AU  - Brian W. Kunkle
AU  - Eden R. Martin
AU  - Omar G. Rodriguez
AU  - Lissette Gomez
AU  - Rui B. Chang
AU  - Carla Vanina Rothlin
AU  - Sourav Ghosh
AU  - Pallavi P. Gopal
AU  - David A. Hafler
AU  - Hongyu Zhao
AU  - Stephen M. Strittmatter
PY  - 2026
DA  - 2026/09/01
JO  - Journal of Alzheimer s Disease
DO  - 10.1177/13872877261480719
UR  - https://doi.org/10.1177/13872877261480719
AB  - Alzheimer’s disease, the most common age-related neurodegenerative disease, is closely associated with both amyloid-ß plaque and neuroinflammation. Two thirds of Alzheimer’s disease patients are females and they have a higher disease risk. Moreover, women with Alzheimer’s disease have more extensive brain histological changes than men along with more severe cognitive symptoms and neurodegeneration. To identify how sex difference induces structural brain changes, we performed unbiased massively parallel single nucleus RNA sequencing on Alzheimer’s disease and control brains focusing on the middle temporal gyrus, a brain region strongly affected by the disease but not previously studied with these methods. We identified a subpopulation of selectively vulnerable layer 2/3 excitatory neurons that that were RORB-negative and CDH9-expressing. This vulnerability differs from that reported for other brain regions, but there was no detectable difference between male and female patterns in middle temporal gyrus samples. Disease-associated, but sex-independent, reactive astrocyte signatures were also present. In clear contrast, the microglia signatures of diseased brains differed between males and females. Combining single cell transcriptomic data with results from genome-wide association studies (GWAS), we identified MERTK genetic variation as a risk factor for Alzheimer’s disease selectively in females. Taken together, our single cell dataset revealed a unique cellular-level view of sex-specific transcriptional changes in Alzheimer’s disease, illuminating GWAS identification of sex-specific Alzheimer’s risk genes. These data serve as a rich resource for interrogation of the molecular and cellular basis of Alzheimer’s disease.
SN  - 1387-2877
SN  - 1875-8908
ER  -