Biomarkers for Nonexudative Age-Related Macular Degeneration and Relevance for Clinical Trials: A Systematic Review

The purpose of the review was to identify structural, functional, blood-based, and other types of biomarkers for early, intermediate, and late nonexudative stages of age-related macular degeneration (AMD) and summarize the relevant data for proof-of-concept clinical trials.

AMD is a leading cause of blindness in the aging population, yet no treatments exist for its most common nonexudative form. There are limited data on the diagnosis and progression of nonexudative AMD compared to neovascular AMD. Our objective was to provide a comprehensive, systematic review of recently published biomarkers (molecular, structural, and functional) for early AMD, intermediate AMD, and geographic atrophy and to evaluate the relevance of these biomarkers for use in future clinical trials.

A literature search of PubMed, ScienceDirect, EMBASE, and Web of Science from January 1, 1996 to November 30, 2020 and a patent search were conducted. Search terms included "early AMD," "dry AMD," "intermediate AMD," "biomarkers for nonexudative AMD," "fundus autofluorescence patterns," "color fundus photography," "dark adaptation," and "microperimetry." Articles were assessed for bias and quality with the Mixed-Methods Appraisal Tool. A total of 94 articles were included (61,842 individuals).

Spectral-domain optical coherence tomography was superior at highlighting detailed structural changes in earlier stages of AMD. Fundus autofluorescence patterns were found to be most important in estimating progression of geographic atrophy. Delayed rod intercept time on dark adaptation was the most widely recommended surrogate functional endpoint for early AMD, while retinal sensitivity on microperimetry was most relevant for intermediate AMD. Combinational studies accounting for various patient characteristics and machine/deep-learning approaches were best suited for assessing individualized risk of AMD onset and progression.

This systematic review supports the use of structural and functional biomarkers in early AMD and intermediate AMD, which are more reproducible and less invasive than the other classes of biomarkers described. The use of deep learning and combinational algorithms will gain increasing importance in future clinical trials of nonexudative AMD.