Summary: Glaucoma progressively damages the optic nerve and retinal ganglion cells, leading to vision loss. Standard care focuses on lowering intraocular pressure, but responses vary. New research from Karolinska Institutet shows that elevated homocysteine is a marker of metabolic disturbance in glaucoma rather than a direct cause. Instead, disrupted one‑carbon metabolism in the retina — affecting the use of vitamins B6, B9 (folate), B12 and choline — appears to contribute to neurodegeneration. Supplementing these nutrients prevented or slowed nerve damage in animal models, and a clinical trial is now recruiting to test the approach in patients.
Researchers have long observed higher homocysteine levels in people with glaucoma and speculated the compound might drive degeneration. The Karolinska team tested that hypothesis in multiple ways. Raising vitreous homocysteine in rats did not accelerate disease beyond a modest, noncausal effect, and genetic and serum data from human cohorts did not link naturally higher homocysteine levels to faster glaucoma progression. Taken together, the evidence indicates homocysteine is a bystander that signals an underlying metabolic problem rather than the root cause.
Detailed metabolic analyses in both human samples and rodent glaucoma models revealed early and sustained dysregulation of one‑carbon metabolism pathways. These pathways require cofactors and precursors — vitamins B6, B9 and B12 plus choline — to support essential biochemical reactions in the retina and optic nerve head. When these pathways are impaired, local retinal metabolism slows, leaving retinal ganglion cells vulnerable to degeneration despite standard pressure‑lowering strategies.
To test whether restoring one‑carbon metabolism protects retinal cells, the researchers supplemented mice and rats with vitamins B6, B9, B12 and choline. The results were striking: in a chronic, slower‑progressing mouse model of primary open‑angle glaucoma, supplementation halted optic nerve degeneration and preserved visual function. In a more aggressive rat model with rapid disease progression, the vitamin regimen significantly slowed neurodegeneration. Importantly, these neuroprotective effects occurred without lowering intraocular pressure, indicating a mechanism distinct from conventional pressure‑reducing therapies.
Based on these preclinical successes, a clinical trial has been initiated to evaluate whether the same B‑vitamin plus choline combination can slow glaucoma progression in people. Recruitment is underway at S:t Eriks Eye Hospital in Stockholm and includes patients with primary open‑angle glaucoma and pseudoexfoliation glaucoma, representing both slower and faster progressing forms of the disease. Further trial details are being provided by Karolinska Institutet.
Key points:
- Homocysteine is a marker, not a driver: Elevated homocysteine levels reflect metabolic dysfunction in the retina rather than directly causing glaucoma.
- One‑carbon metabolism is disrupted: Retina and optic nerve tissues show impaired use of cofactors and precursors required for healthy metabolism.
- Vitamin therapy shows neuroprotection: Combined supplementation with vitamins B6, B9, B12 and choline prevented or slowed retinal ganglion cell loss in animal models.
- Clinical testing is under way: A human trial is recruiting to assess whether this nutritional approach can slow glaucoma progression independently of intraocular pressure lowering.
Source: Karolinska Institutet
Funding: The study received support from the Swedish Research Council, the Swedish Eye Health Fund, the Jeansson Foundations, the Crown Princess Margareta Foundation for the Visually Impaired, the Åke Wiberg Foundation, the Petrus & Augusta Hedlund Foundation, and other contributors.
About this visual neuroscience and glaucoma research news
Author: Press Office
Source: Karolinska Institutet
Contact: Press Office – Karolinska Institutet
Image credit: Neuroscience News
Original research: Open access. “Dysfunctional one‑carbon metabolism identifies vitamins B6, B9, B12, and choline as neuroprotective in glaucoma” by James Tribble et al., Cell Reports Medicine. DOI: 10.1016/j.xcrm.2025.102127
Abstract
Dysfunctional one‑carbon metabolism identifies vitamins B6, B9, B12, and choline as neuroprotective in glaucoma
Glaucoma is characterized by progressive loss of retinal ganglion cells (RGCs) and remains a leading cause of irreversible blindness with no approved neuroprotective therapies. To investigate the association between elevated homocysteine and glaucoma, the study elevated vitreous homocysteine experimentally and observed a modest increase in RGC death following ocular hypertension. Genetic analyses in the UK Biobank and longitudinal serum data showed no causal effect of higher systemic homocysteine on glaucomatous visual field progression, supporting the idea that homocysteine elevation is a pathogenic marker rather than a primary cause.
Further investigation revealed early and sustained dysregulation of genes involved in one‑carbon metabolism in whole retina, optic nerve head and isolated RGCs. This dysregulation affects the interaction of essential cofactors and precursors — vitamins B6, B9, B12 and choline. Supplementation with these nutrients provided neuroprotection in an acute injury model and prevented neurodegeneration while preserving visual function in a chronic glaucoma model, supporting a potential therapeutic route that complements pressure‑lowering treatments.