The Science of Rod-Mediated Dark Adaptation, an Outcome Measure for Age-Related Macular Degeneration: The 2025 Proctor Medal Lecture

Age-related macular degeneration (AMD) degrades central vision in older adults worldwide. To enable precision prevention and early intervention, the longitudinal Alabama Study of Age-related Macular Degeneration 2 (ALSTAR2) seeks functional and imaging outcomes at the aging-AMD interface. ALSTAR2 relies on accurate two-dimensional maps of photoreceptor and retinal pigment epithelium (RPE) distributions and a histology-informed, deposit-driven progression sequence involving dysregulated bi-directional transport between photoreceptors and circulation. This transport is globally assessed by rod-mediated dark adaptation (RMDA), a dynamic measure of rod sensitivity recovery after exposure to a bright light. RMDA measured at the rim of the high-risk macula lutea is affected earlier and is more predictive of AMD onset and progression than steady-state functional measures of rods, cones, and neural circuitry, in both tested and fellow eyes. Delayed RMDA incorporates the Oil Spill hypothesis of drusen formation, which posits that lipoprotein particles constitutively released by RPE are trapped by aged Bruch's membrane and choriocapillaris. Subretinal drusenoid deposit, associated with poor RMDA and risk for advanced AMD, may represent a late-appearing barrier to transport at the level of the RPE. Although RMDA slowing is already underway before routinely visible AMD pathology, some structural and metabolic imaging technologies may assist early detection.