Precuneus amyloid-β deposition involving the association of irritability and cognitive decline: A multi-cohort longitudinal study

BackgroundIrritability is increasingly recognized for its association with cognitive function, though its impact on cognitive decline and underlying mechanisms remain unclear.ObjectiveTo investigate the associations between irritability and cognition, identify potential neurobiological mechanisms.MethodsThis study included three cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 722), the UK Biobank (UKB, N = 405,112), and the China Longitudinal Aging Study (CLAS, N = 240). Participants were classified into irritability-positive (+) and irritability-negative (-) groups based on assessment of irritability.We used Linear mixed-effects models to assess irritability-related cognitive trajectory, Cox regression to estimate cognitive decline, mediation analysis to test the effect of amyloid-β (Aβ) on the relationship between irritability and cognitive decline, and enrichment analysis to identify the underlying pathological mechanisms of irritability.ResultsIrritability was associated with increased cognitive decline in both ADNI (HR = 1.49, 95% CI: 1.12-1.98) and UKB (HR = 1.09, 95% CI: 1.04-1.15) cohorts, with baseline irritability linked to faster Mini-Mental State Examination decline (2.76 versus 1.88). Mediation analysis showed that cerebrospinal fluid (CSF) Aβ mediated 19-24% of irritability's effect on cognitive decline, while precuneus Aβ pathology mediated 30-41%. Imaging analysis revealed significant thinning of the left precuneus cortex in individuals with irritability. Proteomic analysis indicated underlying pathways involving enhanced energy metabolism and suppressed signal transduction, with modifiable factors (air pollution and physical inactivity) associated with irritability-related pathological proteins.ConclusionsOur findings indicate that irritability is significantly associated with cognitive decline. This association may be driven by mechanisms involving precuneus pathology, increased energy metabolism, and suppressed signal transduction, though these results warrant confirmation in future studies.