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Peer-reviewedCC BY 4.0Cell Reports Medicine

Regional brain aging signatures predict mortality through neurovascular immune mechanisms

  • Pei-Lin Lee1
  • Yi-Long Huang1
  • Chih-Kuang Liang2,3,4
  • Wei-Ju Lee1,5
  • Li-Ning Peng1,6
  • Fei-Yuan Hsiao7,8,9
  • Ching-Po Lin10,11,12
  • Liang-Kung Chen1,6,13
13 affiliations
  1. 1Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
  2. 2Center for Geriatrics and Gerontology, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan
  3. 3Division of Neurology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan
  4. 4Department of Geriatric Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
  5. 5Department of Family Medicine, Taipei Veterans General Hospital Yuanshan Branch, Yilan 26444, Taiwan
  6. 6Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
  7. 7Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
  8. 8School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
  9. 9Department of Pharmacy, National Taiwan University Hospital, Taipei 100225, Taiwan
  10. 10Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
  11. 11Brain Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
  12. 12Department of Education and Research, Taipei City Hospital, Taipei 103212, Taiwan
  13. 13Taipei Municipal Gan-Dau Hospital (managed by Taipei Veterans General Hospital), Taipei 112020, Taiwan
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Abstract

Brain aging provides an integrative marker of systemic health, but whether regional patterns outperform whole-brain approaches remains unknown. Here, we show that regional brain age signatures achieve superior mortality prediction through identifiable neurovascular-immune mechanisms in 1,240 community-dwelling adults followed for 10 years (120 deaths). While global brain age independently predicts mortality (hazard ratio [HR], 1.044 per year), a data-driven three-region model combining the left precentral gyrus, left parahippocampal gyrus, and right cerebellum achieves superior discrimination (C-index, 0.81 vs. 0.79, p = 0.032). Integration with plasma proteomics (513 proteins) reveals complement activation and adaptive immune dysregulation as convergent mechanisms. Region-specific vulnerabilities emerge: microvascular dysfunction in the motor cortex, proteostasis failure in the medial temporal structures, and iron dysregulation in the cerebellum. Longitudinal imaging (n = 444) identifies accelerated brain aging phenotypes predicting cognitive decline (HR, 1.558; p = 0.042). These findings establish regional neuroimaging-proteomic integration as a precision strategy linking network-specific vulnerabilities to systemic immune processes.

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Cite

BibTeXRIS
BibTeX
@article{lee2026regional,
  title = {{Regional brain aging signatures predict mortality through neurovascular immune mechanisms}},
  author = {Pei-Lin Lee and Yi-Long Huang and Chih-Kuang Liang and Wei-Ju Lee and Li-Ning Peng and Fei-Yuan Hsiao and Ching-Po Lin and Liang-Kung Chen},
  journal = {Cell Reports Medicine},
  year = {2026},
  month = oct,
  doi = {10.1016/j.xcrm.2026.103096},
  url = {https://doi.org/10.1016/j.xcrm.2026.103096},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Regional brain aging signatures predict mortality through neurovascular immune mechanisms
AU  - Pei-Lin Lee
AU  - Yi-Long Huang
AU  - Chih-Kuang Liang
AU  - Wei-Ju Lee
AU  - Li-Ning Peng
AU  - Fei-Yuan Hsiao
AU  - Ching-Po Lin
AU  - Liang-Kung Chen
PY  - 2026
DA  - 2026/10/07
JO  - Cell Reports Medicine
DO  - 10.1016/j.xcrm.2026.103096
UR  - https://doi.org/10.1016/j.xcrm.2026.103096
AB  - Brain aging provides an integrative marker of systemic health, but whether regional patterns outperform whole-brain approaches remains unknown. Here, we show that regional brain age signatures achieve superior mortality prediction through identifiable neurovascular-immune mechanisms in 1,240 community-dwelling adults followed for 10 years (120 deaths). While global brain age independently predicts mortality (hazard ratio [HR], 1.044 per year), a data-driven three-region model combining the left precentral gyrus, left parahippocampal gyrus, and right cerebellum achieves superior discrimination (C-index, 0.81 vs. 0.79, p = 0.032). Integration with plasma proteomics (513 proteins) reveals complement activation and adaptive immune dysregulation as convergent mechanisms. Region-specific vulnerabilities emerge: microvascular dysfunction in the motor cortex, proteostasis failure in the medial temporal structures, and iron dysregulation in the cerebellum. Longitudinal imaging (n = 444) identifies accelerated brain aging phenotypes predicting cognitive decline (HR, 1.558; p = 0.042). These findings establish regional neuroimaging-proteomic integration as a precision strategy linking network-specific vulnerabilities to systemic immune processes.
SN  - 2666-3791
ER  -