Abstract

INTRODUCTION: Neuroticism is an established risk factor for Alzheimer's disease (AD), yet the molecular mechanisms linking this personality trait to neurodegeneration remain poorly understood. METHODS: We leveraged single-nucleus RNA-sequencing data from longitudinal cohort studies of cognitive aging (n = 655) to investigate the mechanisms mediating the association between neuroticism and AD. RESULTS: We identified two genes associated with neuroticism, both of which are downregulated in excitatory neurons: ADRA1B and LY6E-DT. In addition, we found that neuroticism is associated with enrichment of a specific excitatory neuron subpopulation: Exc.12. Further analysis revealed that Exc.12 partially mediates the relationship between neuroticism and AD, accounting for 12.2% of the total effect. DISCUSSION: The dysregulation of excitatory neurons may represent a key cellular change that links neuroticism to AD.