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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-\u03b2 (A\u03b2) on the relationship between irritability and cognitive decline, and enrichment analysis to identify the underlying pathological mechanisms of irritability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Irritability was associated with increased cognitive decline in both ADNI (HR\u2009=\u20091.49, 95% CI: 1.12\u20131.98) and UKB (HR\u2009=\u20091.09, 95% CI: 1.04\u20131.15) cohorts, with baseline irritability linked to faster Mini-Mental State Examination decline (2.76 versus 1.88). Mediation analysis showed that cerebrospinal fluid (CSF) A\u03b2 mediated 19\u201324% of irritability's effect on cognitive decline, while precuneus A\u03b2 pathology mediated 30\u201341%. 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877261467432","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T12:52:55Z","timestamp":1784811175000},"page":"198-215","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Precuneus amyloid-\u03b2 deposition involving the association of irritability and cognitive decline: A multi-cohort longitudinal study"],"prefix":"10.1177","volume":"113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0888-6243","authenticated-orcid":false,"given":"Yuanyuan","family":"Liu","sequence":"first","affiliation":[{"name":"Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 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