Sex differences in marmoset neurocognitive aging, a nonhuman primate model for brain aging and age‐related neurodegenerative diseases

Abstract

AbstractBackgroundNonhuman primate models of human aging are necessary to understand functional decline and identify vulnerabilities to aging pathologies. Longitudinal studies are critical and common marmosets (Callithrix jacchus) are ideal as they have a short lifespan (∼12 yr) and naturally develop neuropathology relevant to Alzheimer’s disease (AD).MethodWe studied 28 marmosets (14 females) from midlife (∼5 yr old) to old age across four years. Simple discrimination and reversal learning was used to evaluate cognitive performance. Additional yearly tests included motor, stress reactivity, and social behavior assessments. A subset of animals (n = 17, 9 females) were studied for AD‐relevant neuropathology in post‐mortem tissue of the dorsal lateral prefrontal cortex (dlPFC) and CA1 of the hippocampus.ResultMultilevel models revealed age‐related changes for cognitive performance with improved reversal learning during the first three years due to practice followed by decline in the final year with the onset of old age. Cognitive decline was steeper and began earlier for females compared to males. Based on cognitive trajectories which were highly variable across individuals, we categorized marmosets as cognitively impaired or non‐impaired. Mild amyloid β (Aβ) deposition was observed in the dlPFC and CA1 but did not differ between males and females. Aβ burden was higher in cognitively impaired compared to non‐impaired marmosets, but this difference did not reach statistical significance. However, cognitively impaired marmosets showed signs of accelerated brain aging including higher astrogliosis associated with Aβ deposits and dendritic spine loss, both in the dlPFC and hippocampus. In addition, increased activation and changes in microglial phenotypes were observed in the dlPFC.ConclusionLike humans, aging marmosets displayed intra‐individual variability in cognitive decline, neurodegeneration and neuronal aging. Female marmosets showed greater vulnerability to cognitive impairment, which is translationally relevant to the higher prevalence of AD in women. While trajectories of cognitive decline did not strongly map onto Aβ burden for females or males, evidence of accelerated brain aging was found in the impaired marmosets. This study highlights the value of marmosets as a nonhuman primate model of AD to identify vulnerabilities to aging pathologies, such as sex differences.