Serum homocysteine, hemoglobin, and Alzheimer's biomarkers involved in the relationship of folate and vitamin B12 with cognitive function: Findings from the Hubei Memory and Aging Cohort Study

Vitamin B12 and folate deficiency are significant risk factors for cognitive impairment (CI), although the underlying biological mechanisms remain incompletely characterized. We hypothesized that anemia, hyperhomocysteinemia, and plasma Alzheimer's disease biomarkers mediate the relationship between vitamin B12/folate status and CI. Data were analyzed from the Hubei Memory and Aging Cohort Study (2023-2024), which included 1614 community-dwelling older adults in Wuhan, China (mean age 68.52 ± 8.36 years; 58.43% female). Both cross-sectional (n = 1614) and 1-year longitudinal (n = 510) analyses were conducted. Cognitive status was determined through clinical adjudication. Mediation models assessed the roles of hemoglobin (Hb), homocysteine (Hcy), and plasma Alzheimer's disease biomarkers (Aβ40, Aβ42, p-Tau181, p-Tau217, GFAP, NFL). Lower concentrations of folate, vitamin B12, and Hb, and higher concentrations of Hcy, NFL, and GFAP were associated with increased CI risk. Elevated Hcy was correlated with higher concentrations of p-Tau181, GFAP, and NFL, while lower Hb was correlated with higher concentrations of p-Tau181, p-Tau217, GFAP, and NFL. Chain mediation analyses revealed that folate (indirect effect = -0.007, 95% confidence interval: -0.033 to -0.002) and vitamin B12 (indirect effect = -0.009, 95% confidence interval: -0.016 to -0.002) were associated with CI risk sequentially through Hcy and NFL. The folate-Hcy-CI pathway was further supported by longitudinal analysis. Findings suggest that folate and vitamin B12 deficiencies may relate to CI risk through distinct pathways that converge on NFL. Monitoring Hcy and NFL could help identify at-risk individuals, though further validation in intervention studies is warranted.