Elevated Total Homocysteine in All Participants and Plasma Vitamin B12 Concentrations in Women Are Associated With All-Cause and Cardiovascular Mortality in the Very Old: The Newcastle 85+ Study

Abstract

Background: Folate and vitamin B12 are keys to the correct functioning of one-carbon (1-C) metabolism. The current evidence on associations between 1-C metabolism biomarkers and mortality is inconclusive and generally based on younger or institutionalized populations. This study aimed to determine the associations between biomarkers of 1-C metabolism and all-cause and cardiovascular (CVD) mortality in the very old.

Methods: The Newcastle 85+ Study is a prospective longitudinal study of participants aged 85 at recruitment living in Northeast England. Baseline red blood cell folate (RBC folate), plasma vitamin B12, and total homocysteine (tHcy) concentrations were available for 752-766 participants. Associations between biomarkers of 1-C metabolism and all-cause and CVD mortality for up to 9 years were assessed by Cox proportional hazard models and confirmed by restricted cubic splines.

Results: Participants with higher tHcy concentrations had higher risk of death from any cause (hazard ratio [HR] [×10 μmol/L]: 1.24, 95% confidence interval [CI]: 1.10-1.41) and cardiovascular diseases (HR [×10 μmol/L]: 1.23, 95% CI: 1.04-1.45) than those with lower concentrations; and women with higher plasma vitamin B12 concentrations had increased risk of all-cause and cardiovascular mortality (HR [×100 pmol/L]: 1.10, 95% CI: 1.04-1.16) after adjustment for key sociodemographic, lifestyle, and health confounders.

Conclusion: Higher concentrations of tHcy in all participants and plasma vitamin B12 in women were associated with increased risk of all-cause and CVD mortality in the very old. This confirms findings for tHcy in younger populations but the adverse relationships between elevated plasma vitamin B12 concentrations and mortality in this setting are novel and require further investigation.

Figure 1.

Kaplan–Meier plot of the probability of survival for all-cause (A) and cardiovascular mortality (B) by total homocysteine quartiles, and all-cause mortality in women by plasma vitamin B12 quartiles (C) and reference ranges in women (D). Censoring is indicated by crosses.

Figure 2.

Restricted cubic spline curves of dose–response relationship between total homocysteine (A), red blood cell folate (B) and plasma vitamin B12 (C), and all-cause mortality hazard ratios from the fully-adjusted Cox regression models in Supplementary Table 2 and Table 2.

Figure 3.

Restricted cubic spline curves of dose–response relationship between plasma vitamin B12 and all-cause mortality hazard ratios for men and women (A) from fully-adjusted Cox regression models from Table 2, and by <1 and >1 year of follow-up (B) from Supplementary Table 5.