Subretinal drusenoid deposits above the RPE or soft drusen below it are two disease pathways indicated in AMD. Photo: Mohammad Rafieetary, OD. Click image to enlarge.

Multiple risk factors have been identified for age-related macular degeneration (AMD), but pathogenic mechanisms are only partly known. Finding and studying distinct disease pathways within the whole of AMD could facilitate insight into their individual mechanisms. A recent study proposed that there are two distinct disease pathways involving the two major lesions of intermediate AMD: soft drusen beneath the retinal pigmented epithelium (RPE) and subretinal drusenoid deposits (SDD) above the RPE demonstrated in vivo by spectral domain OCT. Those with and without SDD had distinct systemic associations, serum and genetic risks—but few in common.

This prospective study was conducted at two tertiary vitreoretinal referral centers in New York City and involved 126 participants with AMD. There were 62 SDD (with or without soft drusen) individuals and 64 non-SDD (drusen only) individuals, 51 of whom had cardiovascular disease (CVD) or stroke.

SDD was associated with CVD and stroke in 67% of cases, as well as the ARMS2 risk allele and lower high-density lipoprotein (HDL) cholesterol (61mg/dl vs. 69mg/dl), while non-SDD was associated with higher HDL, the CFH risk allele and two lipid risk genes.

The 47% of cases of pure SDD (without drusen) further suggested that SDD is a distinct retinal pathology. Damage from SDD could then lead, along with that of soft drusen, to advanced AMD.

“What we have shown, specifically, is that patients with SDD, with or without drusen, differ significantly from non-SDD eyes in AMD in their associations with CVD and stroke, serum risks and genetic risks, consistent with the concept of distinct disease pathways,” the researchers wrote in their paper. “This is not proof of different cause and effect, but the growing mass of such differences, without a single significant unifying observation to balance it, is striking.”

The study authors noted that they believe that research on the mechanisms of AMD could be guided by studying the risks that apply specifically to only one or the other pathway.

“These distinctions could enable focused attention on specific risks and single pathways, with correspondingly higher chances of success, they concluded. “The specific association of cardiovascular disease and stroke with SDD in particular merits further study.”