Synergistic association of insomnia and anxiety with cognitive impairment and dementia in older adults.

INTRODUCTION: We investigated the synergistic effects of comorbid insomnia and anxiety on cognitive impairment and dementia and explored the underlying plasma biomarker mechanisms. METHODS: We included adults ≥ 60 years from the cross-sectional cohort named The Shanghai Action to Prevent Dementia in the Elderly (SHAPE) and used data from the longitudinal United Kingdom (UK) Biobank for validation. Regression models and additive interactions were used to evaluate the associations between comorbid insomnia and anxiety and cognitive outcomes. Biomarker mediation effects (tau phosphorylated at threonine 217 [p-tau217], glial fibrillary acidic protein [GFAP], and neurofilament light chain [NfL]) were assessed in a SHAPE subcohort. RESULTS: Comorbid insomnia and anxiety were synergistically associated with incident cognitive impairment in the SHAPE cohort. This vulnerability was validated longitudinally in individuals with incident dementia in the UK Biobank cohort. Additionally, p-tau217 and GFAP mediated this association, predominantly driven by p-tau217, with GFAP showing a modest but significant independent contribution. DISCUSSION: Comorbid insomnia and anxiety are synergistically associated with a higher prevalence of cognitive impairment and incidence of dementia. This vulnerability is partially mediated by amyloid pathology, with astrogliosis providing a modest but significant contribution. These findings underscore the need for combined screening and targeted interventions to mitigate dementia risk.