Despite its extensive usage, OCT had yet to identify an early-stage imaging biomarker for age-related macular degeneration (AMD). The timing of drusen buildup in relation to photoreceptor degradation in AMD was unknown pathophysiologically, as are the inherited genetic variations that contribute to these processes. For a study, researchers used OCT, electronic health record data, and genomic data to define the chronological sequence of changes in retinal layer thicknesses in AMD and the epidemiologic and genetic connections between retinal layer thicknesses and AMD.

About 44,823 people from the Biobank (enrollment age range, 40–70 years; 54% women; median follow-up, 10 years). For retinal layer segmentation, the Topcon Advanced Boundary Segmentation method was utilized. First, in a logistic regression model, we linked 9 retinal layer thicknesses to prevalent AMD (present at enrolment) and incident AMD (diagnosed after enrollment) in a Cox proportional hazards model. Following that, we linked AMD-associated genetic variants to retinal layer thicknesses individually and as a polygenic risk score (PRS). All analyses were adjusted for age, age-squared (age2), gender, smoking status, and main ancestry components.

Photoreceptor segment (PS) thinning was detected throughout the study’s participants’ lives, but retinal pigment epithelium (RPE) and Bruch’s membrane (BM) complex thickening began after the age of 57. Each SD of PS thinning and RPE–BM complex thickening was linked to incident AMD. (PS: 1.35; 95% CI: 1.23–1.47; P=3.7 × 1011; RPE–BM complex: 1.14; 95% CI: 1.06–1.22; P=0.00024). The AMD PRS was linked to PS thinning (β, –0.21 SD per twice genetically increased risk of AMD; 95% CI, –0.23 to –0.19; P=2.8 × 10–74), and its relationship with the RPE–BM complex was U-shaped (thinning with AMD PRS less than the 92nd percentile and thickening with AMD PRS more than the 92nd percentile). AMD risk-raising variations Complement Factor H (CFH):rs570618-T, CFH:rs10922109-C, and Age-Related Maculopathy Susceptibility 2 (ARMS2)/High-Temperature Requirement had the best support for genetic linkage. SYN3/Tissue Inhibitor of Metalloprotease 3 (TIMP3):rs5754227-T on RPE–BM complex thickening and Serine Protease 1 (HTRA1):rs3750846-C on PS thinning. PS thinning preceded RPE–BM complex thickening by decades in epidemiology and was the retinal layer most significantly predictive of future AMD risk. AMD risk alleles are linked to lower PS thickness genetically. Overall, our data support the use of PS thinning as an early-stage biomarker for the development of future AMD.