Causal associations between cognitive impairments and retinal diseases: A two-sample Mendelian randomization study

ObjectiveThis study employed a bidirectional two-sample Mendelian randomization approach to investigate the causal links between Alzheimer's disease, Lewy body dementia, vascular dementia, and various retinal diseases.MethodsSummary data from large-scale genome-wide association studies of European ancestry were used to select genetic variants as instrumental variables. Causal estimates were derived using the inverse variance-weighted method, complemented by Mendelian randomization-Egger, weighted median, and weighted mode analyses to ensure robustness.ResultsGenetically predicted Alzheimer's disease was associated with a reduced risk of disorders of the choroid and retina (odds ratio = 0.93, 95% confidence interval: 0.88-0.98), retinal detachments and breaks (odds ratio = 0.90, 95% confidence interval: 0.84-0.97), and retinal detachment with retinal break (odds ratio = 0.84, 95% confidence interval: 0.74-0.95). Lewy body dementia was negatively associated with age-related macular degeneration (odds ratio = 0.88, 95% confidence interval: 0.79-0.98), disorders of the choroid and retina (odds ratio = 0.96, 95% confidence interval: 0.93-0.99), and degeneration of the macula (odds ratio = 0.93, 95% confidence interval: 0.88-0.98). Vascular dementia showed negative associations with age-related macular degeneration (odds ratio = 0.93, 95% confidence interval: 0.87-0.99) and degeneration of the macula (odds ratio = 0.96, 95% confidence interval: 0.93-0.99). Conversely, reverse Mendelian randomization indicated that genetic liability to macular degeneration and choroidal/retinal disorders was causally associated with cognitive performance and a reduced risk of Alzheimer's disease.ConclusionsFindings support inverse causal relationships in which specific dementias may reduce retinal disease risk and vice versa, suggesting complex shared biological mechanisms.