Genetic AMD Risk Greater with Decreased Photoreceptor Layer Thickness

Higher PRS for AMD in those with early or intermediate cases revealed a link with drusen-related features like increased risk of soft drusen presence and larger drusen size. Photo: Mark T. Dunbar, OD. Click image to enlarge. Aging comes with changes to all aspects of health, and the related ocular effects can range in severity. Polygenic risk scores (PRSs) have already been developed for age-related macular degeneration (AMD), although the scores don’t account for if microstructural retinal changes occur in early AMD. Researchers compared retinal microstructural change due to age in people with healthy maculae vs. in those with early AMD to see if this may be a characteristic in early cases.Included in the investigation were individuals aged 55 or older; the group of healthy maculae included 470 participants and those with early (n=87) or intermediate (n=48) AMD were gathered, all taken from the Northern Ireland Sensory Ageing study. It was found that photoreceptor layer thickness decreased with age in all participants, although retinal pigment epithelium (RPE) layer thickness decreased only in those with healthy maculae. A greater PRS was linked with thinner photoreceptor and RPE thickness as well as larger drusen size and soft drusen presence.The authors of the study elaborate on their findings, explaining that photoreceptor thickness decreasing with age in all participants and RPE layer thinning in healthy maculae reflects previous studies performed on healthy populations. They add that decreased photoreceptor thickness was linked with a higher PRS for AMD, suggesting that this layer is driven by genetic influence in the outer retina and choroid either directly or indirectly.They also found that thickening of the RPE was associated with increased Beckman stage, possibly caused by drusen presence, cellular dysmorphia and thick basal laminar deposit. As the authors explain in their paper, “These findings suggest that photoreceptor layer thinning precedes RPE layer thickening in the pathogenesis of AMD.”Included in the analysis were 45 single-nucleotide polymorphisms included for calculation of PRS, and among these, seven rare variants had a relatively large effect size and were located in or near genes related to the complement system; these PRS components are also associated with lipid and extracellular matrix pathways in AMD.“Our findings that the significant associations between AMD PRS and photoreceptor thinning in healthy individuals in our study further indicated the genetic impact on photoreceptor thinning prior to AMD onset,” the authors wrote in their paper.Expanding on this, the team believes that their findings “may support the hypothesis that the link between photoreceptor thinning and RPE thickening is mediated by decreased cholesterol recycling in the photoreceptor outer segment leading to increased cholesterol deposition into the Bruch’s membrane, which over time contributes to drusen deposits.”Click here for the journal source. Tang F, Hogg RE, Higgins BE, et al. Impact of polygenic risk scores on retinal microstructures in early and intermediate age-related macular degeneration: the Northern Ireland Sensory Aging Study. Eye (Lond). May 29, 2025. [Epub ahead of print].