Structural photoreceptor evaluation in age-related macular degeneration. A comprehensive review of methods and clinical significance

Age-related macular degeneration (AMD) is a disease that primarily affects the outer retina, with progressive photoreceptor degeneration and atrophy of the retinal pigment epithelium (RPE). Advances in imaging now enable photoreceptor changes to be detected and quantified with unprecedented sensitivity, whereas comparable biomarkers of RPE dysfunction remain less developed. As such, photoreceptor-based biomarkers are increasingly considered potential surrogates for current clinical trial endpoints. This review examines the current imaging modalities-particularly optical coherence tomography (OCT) and modalities enhanced by adaptive optics (AO) -used to evaluate photoreceptor structure in AMD. We explore the intrinsic value of parameters such as outer nuclear layer thickness, external limiting membrane integrity, photoreceptor inner and outer segment thickness, ellipsoid zone (EZ) integrity, and EZ reflectivity on OCT, and cone density and regularity on AO imaging, highlighting their potential and limitations. While OCT-based metrics are the most accessible in clinical settings, their clinical utility is hampered by inconsistent segmentation protocols and methodological heterogeneity. AO imaging offers unmatched resolution but faces practical barriers to widespread adoption. The field is moving in a promising direction with emerging computational tools and artificial intelligence improving accuracy and scalability. However, progress is contingent on establishing consensus definitions, standardized acquisition and analysis protocols, and normative datasets. Future efforts should focus on translating high-resolution imaging into robust, reproducible biomarkers that can be widely adopted in both clinical practice and therapeutic development.