Elevated Homocysteine and Cognitive Impairment in Parkinson's Disease: A Systematic Review and Meta-Analysis

Homocysteine, a key metabolite in one-carbon metabolism, has been implicated in neurodegeneration and cognitive decline. While its association with Alzheimer's disease has been extensively studied, its role in Parkinson’s disease (PD)-related cognitive impairment remains unclear. We conducted a systematic review and meta-analysis to examine the relationship between plasma homocysteine levels and cognitive dysfunction in PD patients. A systematic search of PubMed, Web of Science, CINAHL, and the Cochrane Library identified 12 eligible studies (n = 1,848). Random-effects meta-analysis showed that PD patients with cognitive impairment had significantly higher homocysteine levels compared to those with normal cognition (mean difference: 3.11 µmol/L; 95% CI: 2.13 to 4.10; p < 0.00001). Subgroup analysis indicated a stronger association in Eastern populations. Meta-regression revealed a positive correlation between disease duration and homocysteine levels but no significant association with L-dopa dosage. Sensitivity analyses supported the robustness of findings, and no major publication bias was detected. Our findings suggest that hyperhomocysteinemia may serve as a modifiable biomarker for cognitive decline in PD, offering potential avenues for early intervention. Moreover, these results highlight homocysteine metabolism as a broader therapeutic target across aging-related neurodegenerative diseases. This study provides translational insights into the systemic metabolic contributions to neurocognitive health.