African green monkeys respond to synthetic Aβ oligomers with persistent Alzheimer’s-like activation

African green monkeys (AGMs) provide a promising alternative to congenic rodent models because of their closer evolutionary relationship to humans and natural genetic variation. They share key physiological and biochemical traits with humans, including neuroanatomy, vascular structure, inflammatory responses, and lifespan. Unlike rodents, AGMs naturally develop Alzheimer’s-like amyloid-β (Aβ) plaques and tau pathology with age. Immunohistochemical studies further show that AGMs inoculated with synthetic Aβ oligomers (AβO) exhibit hyperphosphorylated tau and neuroinflammation one year later, in the absence of overt neurodegeneration. The AGM body size permits collection of cerebrospinal fluid (CSF) and CSF-derived extracellular vesicles (EV) from living individuals, which are key sources of Alzheimer’s disease biomarkers that can be monitored during disease progression. Here, we evaluate AβO treated AGMs at the systems level using proteomics of CSF and phosphatidylserine affinity isolated EVs (EVps). We optimized a workflow to obtain paired CSF and EVps proteomics from <1 mL volumes, i.e., comparable to human liquid biopsy. Our measurements reveal robust, persistent AD-like responses at the biochemical level without overt loss of cognitive function. As such, these findings in AGMs suggest potential alternatives for disease tracking and early detection, and may point to protective mechanisms for limiting disease progression in AD. Aβ oligomer-induced African green monkey models develop early-stage, human AD-like pathological features that can be captured through proteomics of CSF and CSF-derived extracellular vesicles.