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Researchers analyzed blood plasma proteins from 215 individuals with varying stages of age-related macular degeneration (AMD) and controls, identifying four distinct molecular clusters that cross traditional clinical classifications. Neovascular AMD patients divided almost exclusively into two separate protein-based groups, with one showing elevated complement and cellular stress pathways alongside lipid dysfunction, while the other showed primarily lipid-related abnormalities. These molecular differences could not be explained by genetic risk scores, biological aging markers, or clinical features, suggesting neovascular AMD comprises at least two distinct biological subtypes.
Why it matters
This finding challenges the current one-size-fits-all treatment approach for neovascular AMD by revealing that patients with identical clinical presentations may have fundamentally different underlying disease mechanisms. Identifying these proteomic endotypes could enable personalized treatment strategies and help explain why some patients respond differently to current therapies targeting blood vessel growth.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Age-related macular degeneration (AMD) shows substantial clinical heterogeneity that remains unexplained despite extensive genetic and clinical characterization. We evaluated whether proteomic stratification could provide insight beyond clinical phenotype and genetic risk. We performed 384-plex plasma proteomics in a cohort of 215 individuals, including patients with early and late neovascular AMD, other complement-associated retinal diseases, and age-matched controls. Proteome-based reclassification identified four disease-overarching clusters. Neovascular AMD cases were partitioned almost exclusively between two clusters (30/36). Early AMD cases were predominantly assigned to one of these clusters (10/18), whereas only two localized to the other (2/18). Both AMD-associated clusters shared elevated levels of a protein module enriched for lipoprotein-related functions compared to the other clusters. However, the cluster containing both early and neovascular AMD cases showed higher levels of additional protein modules enriched for complement pathways and cellular stress-response pathways compared with the other AMD-associated cluster. Importantly, this molecular divergence in neovascular AMD could not be explained by genetic predisposition (i.e., 52-variant AMD genetic risk score), signatures of biological ageing, nor by other clinical features. Together, these findings support two proteomic endotypes of neovascular AMD with distinct involvement of cellular stress pathways.
Source: Cross-Phenotype Plasma Proteomics Reveals Molecular Heterogeneity in Neovascular AMD