Lee, A. J.; Liu, M.; Yilmaz, E.; Kizil, C.; Oveisgharan, S.; Schneider, J. A.; Bennett, D. A.; Mayeux, R.; Vardarajan, B. N.

Late-life cognitive impairment most commonly occurs in the setting of mixed neurodegenerative and cerebrovascular pathology, yet the molecular programs distinguishing vascular, neurodegenerative, and mixed pathology in the aging human brain remain incompletely defined. We performed neuropathology-stratified proteomic and transcriptomic profiling of postmortem brain tissue from participants in the Religious Orders Study and Rush Memory and Aging Project. Dorsolateral prefrontal cortex proteomics (n = 733) were analyzed alongside bulk RNA sequencing from dorsolateral prefrontal cortex (n = 938), posterior cingulate cortex (n = 569), and anterior caudate (n = 632). Participants were classified into vascular, neurodegenerative, and mixed pathology groups based on comprehensive autopsy assessment. Neurodegenerative and mixed pathology, relative to vascular pathology, showed coordinated upregulation of immune and inflammatory pathways and downregulation of mitochondrial and oxidative phosphorylation programs across molecular layers. Although few individual proteins differed between mixed and neurodegenerative groups, pathway-level analyses identified additional remodeling programs in mixed pathology, including extracellular matrix organization and vesicle-mediated transport. Proteomic co-expression network analysis identified immune-stress modules associated with amyloid burden, tau pathology, and cognitive decline, whereas a mitochondrial bioenergetic module showed relative preservation in vascular pathology. Cross-omics concordance was robust at the pathway level but limited at the level of individual genes and proteins. These findings define conserved molecular programs distinguishing vascular, neurodegenerative, and mixed pathology and demonstrate that pathway-level organization provides a stable framework for interpreting molecular heterogeneity in late-life dementia.