Dry, but not wet, age-related macular degeneration increases Alzheimer's disease risk: Findings from a multidimensional analysis

BackgroundAge-related macular degeneration (AMD) and Alzheimer's disease (AD) share pathophysiological features along the eye-brain axis, but epidemiological, molecular, and causal evidence has not been systematically integrated.ObjectiveTo determine whether AMD, particularly its dry subtype, is causally associated with AD by integrating global epidemiological, bibliometric, molecular, and genetic evidence.MethodsWe analyzed Global Burden of Disease 2021 data, performed a bibliometric analysis, explored shared molecular targets using GeneCards and STRING, and conducted bidirectional two-sample Mendelian randomization (MR) using genome-wide association study summary statistics.ResultsFrom 1990 to 2021, AMD and AD prevalence rose in parallel and peaked in high socio-demographic index regions. Bibliometric analysis of 498 publications showed increasing attention to cellular senescence and MR. Bioinformatics identified 241 shared genes between dry AMD and AD, enriched in complement cascades, MAPK/PI3K-Akt signaling, and lipid metabolism. MR showed that dry AMD causally increased AD risk (OR = 1.14, 95% CI: 1.06-1.24, p = 0.0005), whereas overall AMD showed no causal effect and reverse causality was absent.ConclusionsDry AMD, but not AMD overall, is a causal risk factor for AD, providing genetic support for the eye-brain axis hypothesis. Shared pathways, particularly complement dysregulation, may inform risk stratification and therapeutic development.