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RetiPhenoAge, a retinal aging biomarker, was derived from retinal photographs using deep\u2010learning. Using competing risk analysis, we determined the associations of RetiPhenoAge with cognitive decline and dementia, with the UK Biobank utilized as the replication cohort. The associations of RetiPhenoAge with MRI markers(cerebral small vessel disease [CSVD] and neurodegeneration) and its underlying plasma proteomic profile were evaluated.<\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n \n Of 510 memory\u2010clinic subjects(\n N<\/jats:italic>\n \u00a0=\u00a0155 cognitive decline), RetiPhenoAge associated with incident cognitive decline (subdistribution hazard ratio [SHR] 1.34, 95% confidence interval [CI] 1.10\u20131.64,\n p<\/jats:italic>\n \u00a0=\u00a00.004), and incident dementia (SHR 1.43, 95% CI 1.02\u20132.01,\n p<\/jats:italic>\n \u00a0=\u00a00.036). In the UK Biobank (\n N<\/jats:italic>\n \u00a0=\u00a033 495), RetiPhenoAge similarly predicted incident dementia (SHR 1.25, 95% CI 1.09\u20131.41,\n p<\/jats:italic>\n \u00a0=\u00a00.008). RetiPhenoAge significantly associated with CSVD, brain atrophy, and plasma proteomic signatures related to aging.\n <\/jats:p>\n <\/jats:sec>\n \n DISCUSSION<\/jats:title>\n RetiPhenoAge may provide a non\u2010invasive prognostic screening tool for cognitive decline and dementia.<\/jats:p>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n RetiPhenoAge, a retinal aging marker, was studied in an Asian memory clinic cohort.<\/jats:p>\n <\/jats:list-item>\n \n Older RetiPhenoAge predicted future cognitive decline and incident dementia.<\/jats:p>\n <\/jats:list-item>\n \n It also linked to neuropathological markers, and plasma proteomic profiles of aging.<\/jats:p>\n <\/jats:list-item>\n \n UK Biobank replication found that RetiPhenoAge predicted 12\u2010year incident dementia.<\/jats:p>\n <\/jats:list-item>\n \n Future studies should validate RetiPhenoAge as a prognostic biomarker for dementia.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/alz.14601","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T19:32:52Z","timestamp":1741721572000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["A deep\u2010learning retinal aging biomarker for cognitive decline and incident dementia"],"prefix":"10.1002","volume":"21","author":[{"given":"Ming Ann","family":"Sim","sequence":"first","affiliation":[{"name":"Memory Aging and Cognition Centre Departments of Pharmacology and Psychological Medicine National University of Singapore Singapore Singapore"},{"name":"Department of Anesthesia National University Health System and National University of Singapore, Yong Loo Lin School of Medicine Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yih Chung","family":"Tham","sequence":"additional","affiliation":[{"name":"Centre for Innovation and Precision Eye Health and Department of Ophthalmology Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore"},{"name":"Ocular Epidemiology Research Group Singapore Eye Research Institute Singapore National Eye Centre Singapore Singapore"},{"name":"Ophthalmology and Visual Science Academic Clinical Program Duke\u2010NUS Medical School Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Nusinovici","sequence":"additional","affiliation":[{"name":"Ocular Epidemiology Research Group Singapore Eye Research Institute Singapore National Eye Centre Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ten Cheer","family":"Quek","sequence":"additional","affiliation":[{"name":"Ocular Epidemiology Research Group Singapore Eye Research Institute Singapore National Eye Centre Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Yu","sequence":"additional","affiliation":[{"name":"Ocular Epidemiology Research Group Singapore Eye Research Institute Singapore National Eye Centre Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can Can","family":"Xue","sequence":"additional","affiliation":[{"name":"Ocular Epidemiology Research Group Singapore Eye Research Institute Singapore National Eye Centre Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao Li","family":"Chee","sequence":"additional","affiliation":[{"name":"Ocular Epidemiology Research Group Singapore Eye Research Institute Singapore National Eye Centre Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing Sheng","family":"Peng","sequence":"additional","affiliation":[{"name":"Centre for Innovation and Precision Eye Health and Department of Ophthalmology Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene S. 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