Sex-Specific Effects of Anxiety on Cognition and Activity-Dependent Neural Networks: Insights from (Female) Mice and (Wo)Men

INTRODUCTION: Neuropsychiatric symptoms (NPS), such as depression and anxiety, are observed in 90% of Alzheimer’s disease (AD) patients, two-thirds of whom are women. NPS usually manifest long before AD onset creating a therapeutic opportunity. Here, we examined the impact of anxiety on AD progression and the underlying brain-wide neuronal mechanisms. METHODS: To gain mechanistic insight into how anxiety impacts AD progression, we performed a cross-sectional analysis on mood, cognition, and neural activity utilizing the ArcCreER(T2) x enhanced yellow fluorescent protein (eYFP) x APP/PS1 (AD) mice. The ADNI dataset was used to determine the impact of anxiety on AD progression in human subjects. RESULTS: Female AD mice exhibited anxiety-like behavior and cognitive decline at an earlier age than control (Ctrl) mice and male mice. Brain-wide analysis of c-Fos(+) revealed changes in regional correlations and overall network connectivity in AD mice. Sex-specific memory trace changes were observed; female AD mice exhibited impaired memory traces in dorsal CA3 (dCA3), while male AD mice exhibited impaired memory traces in the dorsal dentate gyrus (dDG). In the ADNI dataset, anxiety predicted transition to dementia. Female subjects positive for anxiety and amyloid transitioned more quickly to dementia than male subjects. CONCLUSIONS: While future studies are needed to understand whether anxiety is a predictor, a neuropsychiatric biomarker, or a comorbid symptom that occurs during disease onset, these results suggest that AD network dysfunction is sexually dimorphic, and that personalized medicine may benefit male and female AD patients rather than a one size fits all approach.