Unveiling the glymphatic system’s role in brain aging: A comprehensive biomarker and modifiable intervention target
Abstract
The focus of this study is to investigate the role of diffusion tensor imaging along the perivascular space (DTI-ALPS) index in brain aging. To address this, we first examined the association of DTI-ALPS with aging hallmarks among 40,488 UK Biobank (UKB) participants. Next, we developed normative brain age models incorporating the DTI-ALPS index from 12,401 healthy UKB adults and validated in UKB-ADNI and UKB-TALENT datasets. Finally, we explored the relationship between brain age gap (BAG) with peripheral organ function, chronic diseases, proteomics, and genetics, while identifying modifiable factors in a longitudinal cohort. The findings revealed that DTI-ALPS index correlated with chronological age, telomere length, brain structure, and cognition. A brain age model integrating the DTI-ALPS index achieved good accuracy in the UKB ( r = 0.756) and replicated well in two independent datasets (UKB-ADNI: r = 0.766; UKB-TALENT: r = 0.724), with choroid plexus volume emerging as an additional contributor. Musculoskeletal health was a key driver for brain aging in females, while pulmonary metrics prevailed in males. Neurodegenerative and metabolic disorders increased BAGs, imparting increased mortality risk. Protein-wide and genome-wide analysis identified 154 BAG-related proteins and 11 loci. Modifiable factors, particularly systolic blood pressure below 120 mmHg, were strongly associated with reduced BAGs. Overall, the DTI-ALPS index is a promising brain aging biomarker, offering insights into links between brain and peripheral health, and highlighting sex-stratified therapeutic strategies. Aggressive blood pressure control may mitigate brain aging and promote long-term brain health.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Yuanyuan Fang
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wenxi Luo
College of Life Science and Technology, Huazhong University of Science and Technology
Hao Huang
Lusen Ran
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Yuqin He
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Chang Cheng
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Yao Yao
Yuxiang Hou
School of Computer Science and Technology, National Engineering Research Center for Big Data Technology and System, Services Computing Technology and System Lab, Cluster and Grid Computing Lab, Huazhong University of Science and Technology
Haibo Zheng
School of Computer Science and Technology, National Engineering Research Center for Big Data Technology and System, Services Computing Technology and System Lab, Cluster and Grid Computing Lab, Huazhong University of Science and Technology
Dengji Pan
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Shabei Xu
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Xiang Luo
Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases
Tingting Qin
Clinical Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Xingjie Hao
Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology
Feng Lu
Department of Medical Oncology, Dana-Farber Cancer Institute
Wei Wang
Minghuan Wang
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology