Even slightly raised levels of the amino acid homocysteine in the blood can result in an increased risk of cardiovascular diseases, as shown in over 80 studies (3). Three different vitamins – vitamin B6, vitamin B9 (folate), and vitamin B12 – are thought to control the level of homocysteine in the blood.
A study results analysis showed that the greatest homocysteine-lowering effect (25% decrease) was achieved by vitamin B9 (folic acid) supplementation (0.5–5 mg/day). An additional 7% reduction (32% decrease) in blood homocysteine levels was demonstrated when vitamin B9 was taken in conjunction with vitamin B12 (mean 0.5 mg/day or 500 mcg/day) (4).
Vitamin B12 deficiency is, according to some evidence, a leading cause of elevated homocysteine levels in people over 60 (5). Before beginning homocysteine-lowering therapy, it is therefore essential to ascertain vitamin B12 status, as well as kidney function, in older people with increased homocysteine levels.
Whether vitamin B12 supplementation lowers the risk of cardiovascular diseases is not yet fully understood. Clinical trials in the future should help provide an answer to this.
Deficiency of vitamin B12 traps vitamin B9 (folate), required for synthesis of DNA, in a form that is unusable. There is evidence that decreased availability of folate results in strands of DNA that are more susceptible to damage. Both vitamin B12 and folate deficiencies result in a diminished capacity for reactions that add methyl groups (‘methylation’) to DNA. Thus, vitamin B12 deficiency may lead to an elevated rate of DNA damage and altered methylation of DNA, both of which are important risk factors for cancer.
A series of studies in young adults and older men indicated that increased levels of homocysteine and decreased levels of vitamin B12 in the blood were associated with a marker of chromosome breakage in white blood cells. In a double-blind placebo-controlled study, the same marker of chromosome breakage was minimized in young adults who were supplemented with 700 micrograms (mcg) vitamin B9 (folic acid) and 7 mcg vitamin B12 daily in cereal for two months (6).
A meta-analysis from 2015 showed that elevated levels of Vitamin B2, B6, B12 and folic acid in serum lowered the risk of renal cell cancer. Still large population studies are missing to support the association (39).
A case-control study in Mexican women (475 cases and 1,391 controls) reported that breast cancer risk for women with high vitamin B12 intake was 68% lower than the risk for those with low intake (7). The association between high dietary vitamin B12 intake and decreased breast cancer risk was stronger in postmenopausal women compared to premenopausal women, though both associations were statistically significant. Because these studies were observational, it cannot be determined whether decreased serum levels of vitamin B12 or low dietary vitamin B12 intakes were a cause or a result of breast cancer. A more recent analysis of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort could not find clear association of Vitamin B12 and folate biomarkers and breast cancer risk. Only a small positive association could be found between Vitamin B12 status and breast cancer risk in women consuming high amounts of alcohol or which had very low folate plasma levels (40).
However, high dietary vitamin B9 (folate) intakes have been associated with reduced risk of breast cancer in several studies, and some studies have reported that vitamin B12 intake may modify this association (8, 9).
Neural tube defects (NTD) may result in devastating and sometimes fatal birth defects, occuring between the 21st and 27th days after conception, a time when many women do not realize they are pregnant (10).
Randomized controlled trials have demonstrated 60–100% reductions in NTD cases when women consumed vitamin B9 (folic acid) supplements in addition to a varied diet during the month before and the month after conception. Increasing evidence indicates that the homocysteine-lowering effect of folic acid plays a critical role in lowering the risk of NTD (11). Homocysteine may accumulate in the blood when there is inadequate folate and/or vitamin B12 for effective functioning of the enzyme, which uses homocysteine to synthesize methionin. Therefore, adequate vitamin B12 intake in addition to folic acid may be beneficial in the prevention of NTD.
A systematic review which looked at Vitamin B12 and NTD could not find a clear, only a moderate, association between low maternal Vitamin B12 levels and NTDs (41). There exist several human studies on cobalamin and NTDs, but they are still not conclusive (42).
Individuals with Alzheimer's disease often have low blood levels of vitamin B12. The reason for this association is not clear. Vitamin B12 deficiency, like vitamin B9 (folate) deficiency, may lead to decreased synthesis of the amino acid methionine, thereby adversely affecting ‘methylation’ reactions, essential for themetabolism of components of nerve cells as well as neurotransmitters. Also, moderately increasedhomocysteine levels as well as decreased folate and vitamin B12 levels have been associated with Alzheimer's disease and vascular dementia.
Some but not all studies have associated elevated homocysteine concentrations or decreased serum levels of vitamin B12 with an increased risk of Alzheimer's disease.
In one study, low serum vitamin B12 (below 150 picomolee/Liter) or vitamin B9 (folate) (below 10 nanomoles/Liter) levels were associated with a doubling in the risk of developing Alzheimer's disease in 370 elderly men and women followed over three years (12). In a sample of 1,092 men and women without dementia followed for an average of ten years, those with higher plasma homocysteine levels at baseline (above 14 micromol/L) had a significantly higher (nearly double) risk of developing Alzheimer's disease and other types of dementia (13). A review on cognitive impairment and Vitamin B12 found an association between low levels of Vitamin B12 and neurodegenerative disease and cognitive impairment. Therapy to improve cognition with Vitamin B12 was only successful when patients were already Vitamin B12 deficient, but more clinical trials are needed to support these results (43).
In other studies, vitamin B12 status was not related to risk of Alzheimer's disease or dementia (14, 15, 16). A randomized, double-blind, placebo-controlled clinical trial in 253 older individuals with plasma homocysteine concentrations equal to or greater than 13 micromol/L found that daily B vitamin supplementation (1 mg vitamin B9, 0.5 mg vitamin B12, and 10 mg vitamin B6) for two years did not affect measures of cognitive performance despite an average 4.36 micromol/L reduction in plasma homocysteine concentrations (17). Another randomized, double-blind, placebo-controlled study in 195 elderly adults reported that oral vitamin B12 supplementation (1 mg daily) for six months had no effect on measures of cognitive function (18).
Observational studies have shown that 30% of patients hospitalized for depression are deficient in vitamin B12 (19). A cross-sectional study of 700 community-living, physically disabled women over the age of 65 found that vitamin B12 deficient women were twice as likely to be severely depressed as non-deficient women (20). A population-based study in 3,884 elderly men and women with depressive disorders found that those with vitamin B12 deficiency were almost 70% more likely to experience depression than those with normal vitamin B12 status (21). The reasons for the relationship between vitamin B12 deficiency and depression are not clear.
Because few studies have examined the relationship of vitamin B12 status and the development of depression over time, it cannot yet be determined if vitamin B12 deficiency plays a causal role in depression. A systematic review and meta-analysis found a that treatment with Vitamin B12 may only be helpful in long-term management of depressive symptoms of special populations (44). However, due to the large extent (‘high prevalence’) of vitamin B12 deficiency in older individuals, it may be beneficial to screen for vitamin B12 deficiency as part of a medical evaluation for depression.
Authored by Dr Peter Engel in 2010, reviewed and revised by Angelika Friedel on 29.06.2017