Role of Folate Metabolism in Neurodegenerative Diseases: Insight from Experimental and Clinical Studies

Folate is a key regulator of one-carbon metabolism (OCM), which supports essential physiological processes, including DNA synthesis, repair, methylation, amino acid homeostasis, and redox balance. It is also crucial for brain health throughout life, from neural tube formation during early development to neurotransmitter synthesis, myelination, neuronal development, synaptic plasticity and cognitive function during later stages of life. Disruption of folate-mediated OCM (FOCM) can adversely affect brain health and contribute to neurodegeneration. In this review, we summarize current evidence linking FOCM dysregulation to neurodegenerative diseases, emphasizing disease-specific mechanisms and the therapeutic potential of modulating folate metabolism, as evidenced by experimental and clinical studies. Disruption of FOCM can lead to oxidative stress, impaired methylation, excitotoxicity, and neuroinflammation, thereby contributing to neurodegenerative diseases. In Alzheimer’s disease, impaired FOCM promotes amyloid-β accumulation, tau pathology, cognitive decline, and vascular dysfunction, consistent with low folate and elevated homocysteine observed clinically, though supplementation outcomes remain mixed. In Parkinson’s disease, folate deficiency and hyperhomocysteinemia exacerbate motor deficits and dopaminergic neurodegeneration via oxidative stress, mitochondrial dysfunction, and NLRP3-mediated inflammation and combined folate and vitamin B12 supplementation may reduce levodopa-associated risks. Elevated homocysteine and aberrant FOCM have also been reported in Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Huntington’s disease and are associated with neuroinflammation, demyelination, neuronal loss, and severe disease phenotypes in these conditions. Overall, maintaining optimal folate levels may be a promising strategy to support brain health and reduce the risk of neurodegenerative disorders.