Neuronal vulnerability to brain aging and neurodegeneration in cognitively impaired marmoset monkeys (Callithrix jacchus)

•Higher Aβ deposit and significant astrogliosis in cognitively impaired marmosets.•Activated microglia with a more complex branching in cognitively impaired marmosets.•Increased phagocytic activity in microglial cells in cognitively impaired marmosets.•Changes in dendritic spine head size and density in cognitively impaired marmosets.•Spine morphometrics correlated with the reversal learning task performance. The investigation of neurobiological and neuropathological changes that affect synaptic integrity and function with aging is key to understanding why the aging brain is vulnerable to Alzheimer's disease. We investigated the cellular characteristics in the cerebral cortex of behaviorally characterized marmosets, based on their trajectories of cognitive learning as they transitioned to old age. We found increased astrogliosis, increased phagocytic activity of microglial cells and differences in resting and reactive microglial cell phenotypes in cognitively impaired compared to nonimpaired marmosets. Differences in amyloid beta deposition were not related to cognitive trajectory. However, we found age-related changes in density and morphology of dendritic spines in pyramidal neurons of layer 3 in the dorsolateral prefrontal cortex and the CA1 field of the hippocampus between cohorts. Overall, our data suggest that an accelerated aging process, accompanied by neurodegeneration, that takes place in cognitively impaired aged marmosets and affects the plasticity of dendritic spines in cortical areas involved in cognition and points to mechanisms of neuronal vulnerability to aging.