Aging is a major risk factor for neurological disease, yet the molecular architecture of human brain aging remains poorly defined. Here, we analyzed more than 10,000 cerebrospinal fluid (CSF) proteomes across multiple cohorts and proteomic platforms to develop a 249-protein CSF aging clock that accurately predicted chronological age and generalized across independent datasets. CSF brain-age acceleration was increased across diverse neurological diseases, associated with blood-brain barrier (BBB) dysfunction, and predictive of longitudinal cognitive decline, neuroimaging progression and dementia conversion. A simplified 30-protein panel retained similar prognostic performance. Biologically, the clock resolved two opposing programs: pro-aging activation of immune, vascular/BBB, extracellular matrix and coagulation pathways, marked by CHI3L1, CD14, VWF, LRG1 and LTBP2, and collapse of anti-aging neuronal-maintenance programs, marked by NPTX2, COL1A2, NID1, CDH8 and PENK. Brain-wide single-cell and regional mapping linked these programs to disease-vulnerable compartments. These findings establish a CSF-based molecular framework for quantifying biological brain aging and predicting neurological disease progression.
Xu, S., Guo, Y., Fang, K., Li, S., Wang, T., li, Y., Zhang, M., Li, H., Miao, Z., Yang, Y., Li, Z.
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