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RMDA is a global measure of dysregulated transport between the circulation and photoreceptors, involving at least seven different steps in a retinoid re-supply route especially needed by rods, and a surrogate for the delivery of other essentials across this route. The choice of functional and imaging outcome measures was informed by a model of AMD pathophysiology based on drusen biology, as discovered in the laboratory using high-quality human donor eyes. Specifically, high-risk drusen in the central retina were thought to result from large lipoproteins constitutively made by the retinal pigment epithelium and impaired in transit to circulation by ageing changes in Bruch\u2019s membrane and choriocapillaris. Imaging studies in ALSTAR\/2 thus included optical coherence tomography (OCT) angiography assessments of choriocapillaris flow signal and OCT assessments of outer bands involved in intercellular transfer (interdigitation zone). Of seven vision tests utilised in ALSTAR2, only RMDA achieved a Minimum Clinically Important Difference at 3 years follow-up. This research highlights the importance of developing functionally valid structural endpoints for use in early and intermediate AMD intervention trials. Research to date supports the idea that functional changes emerge earlier than structural changes in early and intermediate AMD. Clinicaltrials.gov # NCT04112667 (registration date October 7, 2019)<\/jats:p>","DOI":"10.1007\/s44402-026-00124-1","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T18:20:22Z","timestamp":1782152422000},"page":"1272-1288","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Impaired Rod-Mediated Vision is the Functional Hallmark of Ageing and Early and Intermediate Age-Related Macular Degeneration"],"prefix":"10.1007","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3424-011X","authenticated-orcid":false,"given":"Cynthia","family":"Owsley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9769-1538","authenticated-orcid":false,"given":"Christine A.","family":"Curcio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"124_CR1","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1016\/S0161-6420(92)31934-7","volume":"99","author":"BEK Klein","year":"1992","unstructured":"Klein BEK, Klein R, Linton KLP. 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Christine A. Curcio: Research support, Heidelberg Engineering, Hoffman LaRoche; Consulting, Genentech\/ Hoffman LaRoche, Astellas, Boehringer Ingelheim, Character Biosciences, Osanni, Annexon, Mobius, Ripple, Sanofi, Merck, Ikarovec, Espansione.","order":1,"name":"Ethics","label":"Competing Interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}