The results of more than 80 studies indicate that even moderately elevated levels of the amino acid homocysteine in the blood increase the risk of cardiovascular diseases (3). The amount of homocysteine in the blood is regulated by at least three vitamins: vitamin B9 (folate), vitamin B12, and vitamin B6.
Analysis of the results of 12 homocysteine-lowering trials showed vitamin B9 (folic acid) supplementation (0.5–5 mg/day) had the greatest lowering effect on blood homocysteine levels (25% decrease); co-supplementation with vitamin B12 (mean 0.5 mg/day or 500 mcg/day) provided an additional 7% reduction (32% decrease) in blood homocysteine concentrations (4).
Some evidence indicates that vitamin B12 deficiency is a major cause of elevated homocysteine levels in people over the age of 60 (5). Thus, it is important to evaluate vitamin B12 status as well as kidney function in older individuals with elevated homocysteine levels prior to initiating homocysteine-lowering therapy.
Future clinical trials should help to answer whether or not supplemental vitamin B12 lowers risk for cardiovascular diseases.
Cancer
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).
Breast cancer
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.
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)
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.
Alzheimer's disease and dementia
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 the metabolism of components of nerve cells as well as neurotransmitters. Also, moderately increased homocysteine 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).
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).
Depression
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. 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.