Plasma and cerebrospinal fluid proteomics reveal distinct patterns of senescence and neuropathology in aging rhesus macaques.

Aging is the primary risk factor for neurodegenerative disease, yet the protein signatures that distinguish physiological brain aging from pathological decline remain incompletely defined in translational models. Using the targeted NULISAseq proteomic platform, we profiled cerebrospinal fluid (CSF) and plasma from 66 rhesus macaques (Macaca mulatta) spanning adult, pre-geriatric, and geriatric ages, and benchmarked the results against human reference samples. Age-related differences were broader and predominantly positive in plasma, whereas comparatively fewer CSF proteins differed with age. Canonical neurosenescence markers of axonal, astrocytic, and microglial biology, including neurofilaments, GFAP, and TREM2, showed age-related patterns similar to those reported in human aging. Synaptic and barrier proteins behaved differently by compartment: neuronal pentraxins and pleiotrophin were lower in the CSF of older animals, while choroid plexus proteins FOLR1 and IGFBP7 were lower in pre-geriatric animals. While immunohistochemistry confirmed extensive parenchymal amyloid deposition in geriatric brains alongside sparse tau pathology, plasma amyloid-beta and phosphorylated tau species tracked age and cortical amyloid burden more closely than their CSF counterparts. Systemic inflammatory and metabolic stress proteins, including IL6 and GDF15, were higher in older animals, resembling human inflammaging. Finally, we describe a subclustering of geriatric animals based on CSF proteomic signatures that is not explained by chronological age. Together, these results map compartment-specific signatures of senescence and early neuropathology across the non-human primate (NHP) lifespan and support the use of NHP models in translational biomarker studies.