A deep‐learning retinal aging biomarker for cognitive decline and incident dementia

Abstract INTRODUCTION The utility of retinal photography‐derived aging biomarkers for predicting cognitive decline remains under‐explored. METHODS A memory‐clinic cohort in Singapore was followed‐up for 5 years. RetiPhenoAge, a retinal aging biomarker, was derived from retinal photographs using deep‐learning. 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. RESULTS Of 510 memory‐clinic subjects( N = 155 cognitive decline), RetiPhenoAge associated with incident cognitive decline (subdistribution hazard ratio [SHR] 1.34, 95% confidence interval [CI] 1.10–1.64, p = 0.004), and incident dementia (SHR 1.43, 95% CI 1.02–2.01, p = 0.036). In the UK Biobank ( N = 33 495), RetiPhenoAge similarly predicted incident dementia (SHR 1.25, 95% CI 1.09–1.41, p = 0.008). RetiPhenoAge significantly associated with CSVD, brain atrophy, and plasma proteomic signatures related to aging. DISCUSSION RetiPhenoAge may provide a non‐invasive prognostic screening tool for cognitive decline and dementia. Highlights RetiPhenoAge, a retinal aging marker, was studied in an Asian memory clinic cohort. Older RetiPhenoAge predicted future cognitive decline and incident dementia. It also linked to neuropathological markers, and plasma proteomic profiles of aging. UK Biobank replication found that RetiPhenoAge predicted 12‐year incident dementia. Future studies should validate RetiPhenoAge as a prognostic biomarker for dementia.