Reduced retinal thickness and risk of Alzheimer’s disease: a bidirectional two-sample Mendelian randomization study

Objectives : Observational studies have suggested associations between retinal layer thinning and increased susceptibility to Alzheimer’s disease (AD), but causal inference remains inconclusive. This study aimed to investigate potential genetic causality between inner retinal layer (IRL) thickness, specifically the retinal nerve fiber layer (RNFL) and the ganglion cell inner plexiform layer (GCIPL), and AD risk. Methods : We conducted a bidirectional two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary statistics for RNFL/GCIPL thickness (n = 31,434; UK Biobank) and AD status (39,106 cases vs. 401,577 controls; European Alzheimer and Dementia Biobank). Replication was performed in an independent AD cohort (35,274 cases vs. 59,163 controls). The inverse-variance weighted (IVW) method was used as the primary analytical approach. Results : No significant associations were found between retinal thickness and AD risk (RNFL: odds ratio [OR]IVW = 1.001, 95% confidence interval [CI] = 0.986-1.017, P = 0.883; GCIPL: ORIVW = 1.008, 95% CI = 0.997-1.019, P = 0.172). Reverse MR analyses also showed no causal effect of genetic liability to AD on retinal thickness (RNFL: ORIVW = 0.907, 95% CI = 0.786-1.046, P = 0.179; GCIPL: ORIVW = 1.014, 95% CI = 0.828-1.242, P = 0.890). These findings were consistent in replication analyses (RNFL: ORIVW = 1.015, 95% CI = 0.987-1.043, P = 0.305; GCIPL: ORIVW = 1.014, 95% CI = 0.991-1.037, P = 0.237). Conclusion : This MR analysis found no evidence of a causal genetic relationship between IRL thickness variations and AD. Future investigations should focus on trans-ethnic populations, longitudinal studies, and multimodal retinal phenotyping within GWAS cohorts to further clarify this relationship.