Vitamin B12, homocysteine levels tied to neurocognitive decline in healthy adults

Low serum levels of vitamin B12 and high concentrations of homocysteine appears to aggravate the risk of progression to neurocognitive disorder (NCD) among cognitively healthy adults, a recent Singapore study has found.

Of the 690 cognitively normal adults (aged ≥55 years, 64.1 percent women) who participated in the study, 5.7 percent (n=39) developed NCD over 4.5 years of follow-up. Most NCD cases were characterized as mild cognitive impairment (n=34), while five patients progressed to dementia. All participants were enrolled from the Singapore Longitudinal Aging Study. [Nutrients 2022;14:3535]

Compared with those who remained cognitively normal, participants who progressed to NCD had significantly lower baseline levels of serum vitamin B12 (mean, 420 vs 510 pmol/L; p=0.026) and one-carbon index values (Z-score: –0.444 vs –0.001; p=0006).

In contrast, baseline homocysteine levels were elevated in patients who developed NCD (14.6 vs 12.9 µmol/L; p=0.018).

Similarly, NCD patients were more likely to be in the bottom two quartiles of vitamin B12, the lowest quartile of one-carbon index, and the top two quartiles of homocysteine concentrations as compared with those who remained cognitively healthy.

These findings were confirmed by logistic regression analysis, which showed that each standard deviation (SD) decrease in vitamin B12 more than doubled the odds of NCD (odds ratio [OR], 2.10, 95 percent confidence interval [CI], 1.26–3.52; p=0.005).

A similar effect was reported for one-carbon index (OR, 1.67, 95 percent CI, 1.0–2.64; p=0.027) and homocysteine (OR, 1.96, 95 percent CI, 1.18–3.24; p=0.009).

The role of folate

In contrast, statistical analysis revealed no role of folate concentrations in NCD development (OR, 0.94, 95 percent CI, 0.64–1.39; p=0.776). Compared with the highest quartile of folate concentrations (≥14.8 nmol/L), those in the first (p=0.914), second (p=0.947), or third (p=0.794) quartiles saw no significant change in the likelihood of NCD.

However, closer analysis revealed that vitamin B12 levels had a modulating effect on the interaction between folate and NCD risk. High folate levels in the presence of low vitamin B12 emerged as a strong risk factor for NCD development, aggravating such odds by nearly fourfold (OR, 3.81, 95 percent CI, 1.04–13.9; p=0.044) as compared with normal levels for both biomarkers.

In contrast, normal folate levels in the presence of low vitamin B12 had no impact on NCD risk.

“The interactions between B-vitamins and homocysteine and their roles in cognition are complex. Many factors may modify cognitive outcomes of B-vitamins and homocysteine-lowering exposure, including age and clinical characteristics including folate status of the total population,” the researchers said.

“Considering the fact that many countries mandate folate fortification of food products, investigators and clinicians should therefore be particularly concerned about the potentially deleterious cognitive effect of high folate in the presence of low B12,” they added.

Nevertheless, further studies are necessary to better understand the interplay between vitamin B12, homocysteine, folate, and one-carbon index in the development of cognitive conditions.