Sex differences in cognitive aging: a 4-year longitudinal study in marmosets

Abstract

Longitudinal studies are essential to understand healthy and pathological neurocognitive aging such as Alzheimer's Disease, but longitudinal designs are rare in both humans and non-human primate models of aging because of the difficulty of tracking cognitive change in long-lived primates. Common marmosets (Callithrix jacchus) are uniquely suited for aging studies due to their naturally short lifespan (10-12 years), sophisticated cognitive and social abilities and Alzheimer Disease-like neuropathology. We report the first longitudinal study of cognitive aging in marmosets (N = 28) as they transitioned from middle- (∼5 years) to old age (∼9 years). We characterized aging trajectories using reversal learning with different stimuli each year. Marmosets initially improved on cognitive performance due to practice, but worsened in the final year, suggesting the onset of age-related decline. Cognitive impairment emerged earlier in females than males and was more prominent for discrimination than for reversal learning. Sex differences in cognitive aging could not be explained by differences in motivation or motor abilities, which improved or remained stable across aging. Likewise, males and females did not differ in aging trajectories of overall behavior or reactivity to a social stressor, with the exception of a progressive decline in the initiation of social behavior in females. Patterns of cognitive aging were highly variable across marmosets of both sexes, suggesting the potential for pathological aging for some individuals. Future work will link individual cognitive trajectories to neuropathology in order to better understand the relationships between neuropathologic burden and vulnerability to age-related cognitive decline in each sex.

Keywords: Aging; Cognition; Marmoset; Nonhuman primate; Reversal learning; Sex difference.

Figure 1.. Study Timeline (A) and Apparatuses (B, C).

A: Cognitive testing in the format of Discrimination and Reversal testing occurred all 4 years with 3 stimuli sets per year. Motor testing was administered each year following completion of cognitive testing. Social separation testing occurred on one day per year during years 1 to 3 and did not overlap with any other testing. Behavior was observed weekly in the home cage. B: Cognitive apparatuses: CANTAB touchscreen (left) and WGTA (right); C: Motor apparatuses: Hill (left) and Valley (right).

Figure 2.. Sex differences in cognitive aging trajectories in marmosets.

Trials to criterion for each year of testing for males (blue) and females (red) on discrimination (A&B) and reversal (C&D). Points represent averaged scores for individual marmosets within each year. Lines represent average aging trajectories from multilevel growth models reported in Table A.5. Error types for discrimination (B) and reversal (D) are presented as means and SEM. #p < 0.065. Y-axes are inverted for A & C for readability.

Figure 3.. Aging trajectories for non-cognitive variables in marmosets.

Aging Trajectories in males (blue) and females (red) for: the proportion of omissions on all cognitive trials (A), response times for discrimination (B) and reversal (C) (Top panel); Motor accuracy and latency (D-E, Middle panel); Homecage behaviors (F-I, Bottom panel). Points represent averaged scores for individual marmosets. Lines represent average aging trajectories from multilevel growth models reported in Table A.6. Y-axes are inverted for B, C & E for readability.

Figure 4.. Behavioral and Physiological Responses to Social Separation Test.

Aging trajectories for males (blue) and females (red) for measures of behavioral (A-C) and physiological (D-E) reactivity, calculated as difference between pre-separation baseline (BL) and total separation score. Positive values represent increase from BL during separation and negative values represent decrease from BL. Zero represents no change from BL, which is indicated with a dotted line. Points represent averages scores for individual marmosets within each year. Lines represent average aging trajectories from multilevel growth models reported in Table A.6. Y-axes are inverted for B, C, D & E for readability.