The Effect of Acetylcholinesterase Inhibitors and N-Methyl-D-Aspartate Receptor Antagonists on the Risk of Development and Progression of Age-Related Macular Degeneration

Abstract

Purpose: To investigate whether memantine or acetylcholinesterase inhibitors are associated with reduced risk of developing age-related macular degeneration (AMD) and of progression from nonexudative to exudative AMD. Methods: This retrospective cohort study used data from the TriNetX US Collaborative Network between 2008 and 2023. Adults 50 years and older were included and categorized into AMD-naïve and dry AMD cohorts. Exposure groups were defined by outpatient prescriptions for acetylcholinesterase inhibitors (donepezil, rivastigmine, or galantamine) or memantine. Each exposure group was propensity score–matched 1:1 to unexposed controls based on demographic and clinical characteristics. Outcomes were incident AMD in the AMD-naïve cohort and incident exudative AMD in the dry AMD cohort at least 1 year after the prescription. Risk ratios (RRs) and 95% CIs were estimated, and memantine was compared with acetylcholinesterase inhibitors in a head-to-head analysis. Results: Among AMD-naïve patients, acetylcholinesterase inhibitor use (n = 35 397) and memantine use (n = 13 576) were associated with lower AMD incidence compared with matched controls (RR, 0.490; 95% CI, 0.442–0.543; P < .001; and RR, 0.532; 95% CI, 0.448–0.630; P < .001, respectively). In patients with dry AMD, both acetylcholinesterase inhibitors and memantine were associated with reduced progression to exudative AMD (RR, 0.448; 95% CI, 0.357–0.562; P < .001; and RR, 0.552; 95% CI, 0.362–0.842; P = .005). In head-to-head comparisons, similar risks for incident AMD were seen with memantine and acetylcholinesterase inhibitors (RR, 0.929; 95% CI, 0.762–1.132; P = .46) and progression to exudative AMD (RR, 1.198; 95% CI, 0.720–1.994; P = .49). Conclusions: Memantine and acetylcholinesterase inhibitors were associated with a reduced risk of AMD development and progression. These findings support further investigation into shared neuroprotective pathways and potential drug repurposing.