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

Abstract

Background: Neuropsychiatric symptoms, such as depression and anxiety, are observed in 90% of patients with Alzheimer's disease (AD), two-thirds of whom are women. Neuropsychiatric symptoms usually manifest long before AD onset creating a therapeutic opportunity. Here, we examined the impact of anxiety on AD progression and the underlying brainwide neuronal mechanisms.

Methods: To gain mechanistic insight into how anxiety affects AD progression, we performed a cross-sectional analysis on mood, cognition, and neural activity using the ArcCreER^T2 x eYFP (enhanced yellow fluorescent protein) x amyloid precursor protein/presenilin 1 (APP/PS1) (AD) mice. The Alzheimer's Disease Neuroimaging Initiative dataset was used to determine the impact of anxiety on AD progression in humans.

Results: Female APP/PS1 mice exhibited anxiety-like behavior and cognitive decline at an earlier age than control mice and male mice. Brainwide analysis of c-Fos⁺ revealed changes in regional correlations and overall network connectivity in APP/PS1 mice. Sex-specific eYFP⁺/c-Fos⁺ changes were observed; female APP/PS1 mice exhibited less eYFP⁺/c-Fos⁺ cells in dorsal CA3, whereas male APP/PS1 mice exhibited less eYFP⁺/c-Fos⁺ cells in the dorsal dentate gyrus. In the Alzheimer's Disease Neuroimaging Initiative dataset, anxiety predicted transition to dementia. Female participants positive for anxiety and amyloid transitioned more quickly to dementia than male participants.

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 there are sex differences in AD network dysfunction and that personalized medicine may benefit male and female patients with AD rather than a one-size-fits-all approach.

Keywords: Arc; Engrams; Hippocampus; Immediate early gene; Memory; Sex differences.