Neuroretinal and Retinal Pigment Epithelium Changes and Susceptibility to Age-Related Macular Degeneration: Insights from the Longitudinal ALIENOR Study.

Objective: We assessed the associations of macular layer thicknesses, measured using spectral-domain (SD) OCT, with incident age-related macular degeneration (AMD) and AMD polygenic risk scores (PRSs). Methods: Population-based cohort study. Methods: A total of 653 participants from the ALIENOR study, with biennial eye imaging from 2009 through 2024. Methods: Macular layer thicknesses of 8 distinct layers were automatically segmented based on SD-OCT imaging. Total and pathway-specific PRSs were calculated from previous AMD genome-wide association studies summary statistics. Associations of macular layer thicknesses with incident intermediate and advanced AMD were analyzed using time-dependent Cox proportional hazards models. Associations of macular layer thicknesses with PRS were assessed using linear mixed models. Methods: Incident intermediate and advanced AMD based on fundus color photographs and SD-OCT. Results: Mean age at first OCT examination of the 653 participants was 82.2 ± 4.2 years, 61.3% of which were women. In multivariable adjusted models, incident intermediate AMD was associated with thicker retinal pigment epithelium (RPE)-Bruch membrane (BM) complex in the 1-mm central circle (hazard ratio [HR], 1.13 for 1-μm increase; P = 8.08 × 10-4 with false discovery rate [FDR] correction). Incident advanced AMD was associated with thicker RPE-BM complex in both the central (HR, 1.09; PFDR = 0.005) and inner circle (1- to 3 mm; HR, 1.28; PFDR = 1.61 × 10-5). Over the study period, RPE-BM complex thickening in the inner circle was more pronounced in individuals with high total PRS (β = 0.06 μm/year for 1-standard deviation increase; PFDR = 1.61 × 10-10), high complement pathway PRS (β = 0.04 μm/year; PFDR = 3.23 × 10-5), high lipid pathway PRS (β = 0.03 μm/year; PFDR = 3.74 × 10-4), and ARMS2 (β = 0.03 μm/year, PFDR = 0.002). High total PRS and high complement-specific PRS were associated with thinner photoreceptor segment layer (PSL) at baseline and longitudinal thinning of the outer nuclear layer. Conclusions: These findings highlight RPE-BM complex thickening in the pathophysiologic sequence of AMD. Further longitudinal studies are needed, in particular to determine the value of RPE-BM thickening and PSL thinning measured using SD-OCT for the clinical follow-up of patients with AMD.

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