B Vitamins & Folate

Much of the research into the importance of folate and B12 levels has centered on seniors, and there is now quite a lot of research pointing to the need for adequate levels of these vitamins for maintaining cognitive functioning as you get older. In particular, high levels of homocysteine increase the risk of developing Alzheimer’s, and these go hand-in-hand with low levels of B12 and folate. Homocysteine is produced by the breakdown of a dietary protein called methionine, and B-vitamins are required to convert homocysteine back to methionine. Mouse research indicates that increased levels of homocysteine impair cognition through microvascular changes in the hippocampus. Greater brain atrophy is also found in those with high levels of homocysteine.

Elevated levels of homocysteine are not only associated with a significantly greater risk of developing Alzheimer's, they also dramatically increase the risk for stroke and vascular dementia.

Excitingly, though, a study found that vitamin B supplements markedly reduced brain atrophy in older adults with mild cognitive impairment, offering hope that they may be effective in delaying the development of Alzheimer’s. The benefits were greatest for those with the highest levels of homocysteine.

Higher levels of homocysteine are also linked with smoking.

Folic acid levels are of course also regarded as crucial when the brain is developing, which is why pregnant women are urged to take supplements, and why some countries fortify their bread with it.

There has been much less research on the effects of B-vitamins outside of the areas of prenatal development and age-related cognitive impairment and dementia. However, one study, carried out in a country which doesn't fortify its flour with folic acid, found significant academic achievement between those in the top third of folic acid intake and those in the bottom third.

Although the evidence for the age-related cognitive benefits of B12 and folate is greater than for any other supplement, not all studies have come out proclaiming their value. The inconsistencies may be explained by a finding that seniors with normal levels of vitamin B12 performed better if folate level was high, but when vitamin B12 was low, high levels of folate were associated with poor cognitive performance, as well as a greater probability of anemia.

Folate is a water-soluble B vitamin found particularly in citrus fruit, green leafy vegetables, whole-wheat bread, water-soluble dried beans and peas; however, they are often destroyed by cooking or processing. In the United States, Canada and Australia, flour is fortified with folic acid. Vitamin B12 is naturally found in animal foods including fish, milk and milk products, eggs, meat, and poultry. Vitamin B12 is often deficient in older people.

A study involving 266 people with mild cognitive impairment (aged 70+) has found that B vitamins are more effective in slowing cognitive decline when people have higher omega 3 levels.

Participants were randomly selected to receive either a B-vitamin supplement (folic acid, vitamins B6 and B12) or a placebo pill for two years. The vitamins had little to no effect for those with low levels of omega-3 fatty acids, but were very effective for those with high baseline omega-3 levels.

Levels of DHA appeared to be more important than levels of EPA, but more research is needed to confirm that.

The finding may help to explain why research looking at the effects of B vitamins, or the effects of omega-3 oils, have produced inconsistent findings.

The study followed research showing that B vitamins can slow or prevent brain atrophy and memory decline in people with MCI, and they were most effective in those who had above average blood levels of homocysteine.


The study involved 104 healthy older adults (average age 87) participating in the Oregon Brain Aging Study. Analysis of the nutrient biomarkers in their blood revealed that those with diets high in omega 3 fatty acids and in vitamins C, D, E and the B vitamins had higher scores on cognitive tests than people with diets low in those nutrients, while those with diets high in trans fats were more likely to score more poorly on cognitive tests.

These were dose-dependent, with each standard deviation increase in the vitamin BCDE score ssociated with a 0.28 SD increase in global cognitive score, and each SD increase in the trans fat score associated with a 0.30 SD decrease in global cognitive score.

Trans fats are primarily found in packaged, fast, fried and frozen food, baked goods and margarine spreads.

Brain scans of 42 of the participants found that those with diets high in vitamins BCDE and omega 3 fatty acids were also less likely to have the brain shrinkage associated with Alzheimer's, while those with high trans fats were more likely to show such brain atrophy.

Those with higher omega-3 scores also had fewer white matter hyperintensities. However, this association became weaker once depression and hypertension were taken into account.

Overall, the participants had good nutritional status, but 7% were deficient in vitamin B12 (I’m surprised it’s so low, but bear in mind that these are already a select group, being healthy at such an advanced age) and 25% were deficient in vitamin D.

The nutrient biomarkers accounted for 17% of the variation in cognitive performance, while age, education, APOE genotype (presence or absence of the ‘Alzheimer’s gene’), depression and high blood pressure together accounted for 46%. Diet was more important for brain atrophy: here, the nutrient biomarkers accounted for 37% of the variation, while the other factors accounted for 40% (meaning that diet was nearly as important as all these other factors combined!).

The findings add to the growing evidence that diet has a significant role in determining whether or not, and when, you develop Alzheimer’s disease.

In a small study, 266 older adults with mild cognitive impairment (aged 70+) received a daily dose of 0.8 mg folic acid, 0.5 mg vitamin B12 and 20 mg vitamin B6 or a placebo for two years. Those treated with B vitamins had significantly lower levels of homocysteine at the end of the trial (high homocysteine is a known risk factor for age-related cognitive decline and dementia). Moreover, this was associated with a significantly slower rate of brain shrinkage.

However, while there were significant effects on homocysteine level, brain atrophy, and executive function, it wasn’t until results were separated on the basis of baseline homocysteine levels that we get really dramatic results.

It was the group with high homocysteine levels at the start of the study who really benefited from the high doses of B vitamins. For them, brain atrophy was cut by half, and there were clear benefits in episodic memory, semantic memory, and global cognitive function, not just executive function. Among those with high baseline homocysteine who received the placebo, significant cognitive decline occurred.

The level of B vitamins in the supplements was considerably greater than the recommended standard. However, caution must be taken in dosing yourself with supplements, because folic acid can have negative effects. Better to try and get your diet right first.

A longer and larger follow-up study is now planned, and hopefully that will tell us if such treatment can keep MCI developing into Alzheimer’s.

Most research into the importance of folate and B12 levels has centered on seniors, and it does seem clear now that having adequate levels of these vitamins is important for maintaining cognitive functioning as you get older. Folic acid levels are of course also regarded as crucial when the brain is developing, which is why pregnant women are urged to take supplements, and why some countries fortify their bread with it. There is less research in the extensive ground between these two end-points.

A Swedish study involving 386 15-year-olds has now found that those in the top third of folic acid intake (more than 253 micrograms per day for girls and 335 for boys) performed significantly better on their school grades compared to those in the bottom third (less than 173 micrograms folic acid per day for girls and 227 for boys).

Interestingly, while homocysteine levels in the blood were initially significant, this association disappeared after other significant predictors (gender, smoking, and SES) were controlled for. Neither was a genotype linked to higher homocysteine levels (MTHFR 677 TT homozygosity) significantly related to academic achievement. Low folate and B12 levels are associated with higher homocysteine levels in the blood, and there is evidence that it is this increase in homocysteine that is the reason for the cognitive impairment seen in age-related cognitive decline. This finding, then, suggests that this is only one part of the story.

Sweden does not fortify flour with folic acid as the United States, Canada and Australia do. Folate is a B vitamin found particularly in citrus fruit, green leafy vegetables, whole-wheat bread, and dried beans and peas; however, they are often destroyed by cooking or processing.

The sum of school grades in 10 core subjects obtained in the final semester of compulsory 9 years of schooling was used as the measure of academic achievement

A seven-year study involving 271 Finns aged 65-79 has revealed that increases in the level of homocysteine in the blood were associated with increasing risk of developing Alzheimer’s (each micromolar increase in the concentration of homocysteine increased the risk of Alzheimer's by 16%), while increases in the level of vitamin B12 decreased the risk (each picomolar increase in concentration of B12 reduced risk by 2%). A larger study is needed to confirm this. 17 people (6%) developed Alzheimer’s over the course of the study.

Still, these results are consistent with a number of other studies showing greater risk with higher homocysteine and lower B12. High levels of vitamin B12 are known to lower homocysteine. However, studies directly assessing the effects of B12 supplements have had mixed results. Low levels of B12 are common in the elderly.

A two-year study involving 271 older adults (70+) with mild cognitive impairment has found that the rate of brain atrophy in those taking folic acid (0.8 mg/d), vitamin B12 (0.5 mg/d) and vitamin B6 (20 mg/d), was significantly slower than in those taking a placebo, with those taking the supplements experiencing on average 30% less brain atrophy. Higher rates of atrophy were associated with lower cognitive performance. Moreover those who with the highest levels of homocysteine at the beginning of the trial benefited the most, with 50% less brain shrinkage. High levels of homocysteine are a risk factor for Alzheimer’s, and folate, B12 and B6 help regulate it.

The finding that atrophy can be slowed in those with MCI offers hope that the treatment could delay the development of Alzheimer’s, since MCI is a major risk factor for Alzheimer’s, and faster brain atrophy is typical of those who go on to develop Alzheimer’s.

A European trial involving 225 patients with mild Alzheimer's has found that those who drank Souvenaid (a cocktail of uridine, choline and the omega-3 fatty acid DHA, plus B vitamins, phosopholipids and antioxidants) for 12 weeks were more likely to improve their performance in a delayed verbal recall task. 40% of the Souvenaid group showed improved performance compared to 24% of the placebo group. Those with the mildest cases of Alzheimer’s showed the most improvement. There was no improvement on the more general ADAS-cog test. Three further clinical trials, one in the U.S. and two in Europe, are now underway.

Scheltens, P. et al. 2010. Efficacy of a medical food in mild Alzheimer's disease: A randomized, controlled trial. Alzheimer's & Dementia, 6 (1), 1-10.

A preliminary study suggests that a regime of high doses of folic acid, B12 and B6 reduces levels of homocysteine in people with mild to moderate Alzheimer’s. A larger study, recruiting 400 participants from all over the U.S., is to be undertaken to assess whether such a vitamin regime can slow the progression of Alzheimer's disease. In the meantime, it is not advised that people take high doses of these vitamins, as there are possible side-effects, including peripheral nerve damage.

[723] Bell, K., Sano M., Aisen P. S., Egelko S., Andrews H., Diaz-Arrastia R., et al.
(2003).  A pilot study of vitamins to lower plasma homocysteine levels in Alzheimer disease.
The American Journal of Geriatric Psychiatry: Official Journal of the American Association for Geriatric Psychiatry. 11(2), 246 - 249.

The nutrient choline is known to play a critical role in memory and brain function by positively affecting the brain's physical development through increased production of stem cells (the parents of brain cells). New research demonstrates that this occurs through the effect of choline on the expression of particular genes. The important finding is that diet during pregnancy turns on or turns off division of stem cells that form the memory areas of the brain. Developing babies get choline from their mothers during pregnancy and from breast milk after they are born. Other foods rich in choline include eggs, meat, peanuts and dietary supplements. Breast milk contains much more of this nutrient than many infant formulas. Choline is a vitamin-like substance that is sometimes treated like B vitamins and folic acid in dietary recommendations.A choline food database is available at: www.nal.usda.gov/fnic/foodcomp.

Older news items (pre-2010) brought over from the old website

Vitamin B12 may protect the brain in old age

A five-year study of 107 older adults (61—87) has found that those who had higher vitamin B12 levels were six times less likely to experience brain shrinkage compared with those who had lower levels of the vitamin in their blood, even though none of them had vitamin B12 deficiency. Vitamin B12 is found in meat, fish and milk, and is often deficient in older people.

[516] Vogiatzoglou, A., Refsum H., Johnston C., Smith S. M., Bradley K. M., de Jager C. A., et al.
(2008).  Vitamin B12 status and rate of brain volume loss in community-dwelling elderly.
Neurology. 71(11), 826 - 832.


B-vitamin deficiency may cause vascular cognitive impairment

A new mouse study helps clarify the association between homocysteine, folate & B12, and cognitive impairment. The study found that mice fed a diet deficient in folate and vitamins B12 and B6 demonstrated significant deficits in spatial learning and memory compared with normal mice, developed plasma homocysteine concentrations that were seven-fold higher, and showed smaller capillary length and density in blood vessels in the hippocampus. Homocysteine is produced by the breakdown of a dietary protein called methionine; B-vitamins are required to convert homocysteine back to methionine. A third group of mice were fed a diet enriched with methionine. These mice showed similar, but less pronounced effects. The findings indicate that increased levels of homocysteine, produced by low intake of folate and B vitamins, impairs cognition through microvascular changes.

[1025] Troen, A. M., Shea-Budgell M., Shukitt-Hale B., Smith D. E., Selhub J., & Rosenberg I. H.
(2008).  B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice.
Proceedings of the National Academy of Sciences. 105(34), 12474 - 12479.

Full text is available at http://www.pnas.org/content/105/34/12474.abstract

How food affects the brain

I’ve reported on quite a lot of studies finding beneficial effects of one food or another on the brain. Now a researcher has analyzed more than 160 studies about food's effect on the brain, and here’s the bottom line. He comes out for omega-3 fatty acids, as both improving synaptic plasticity and the expression of several molecules proteins to learning and memory, as well as protecting against attention-deficit disorder, dyslexia, dementia, depression, bipolar disorder and schizophrenia. He suggests it’s better to get it from food than supplements (which is always recommended). Salmon, walnuts and kiwi fruit are all good sources. They’re still working out which fatty acids are most important, but one is definitely docosahexaenoic acid, or DHA — which like vitamin C we’re not good at making for ourselves; we have to ingest it. He also concludes that diets high in trans fats and saturated fats are bad for cognition.
Studies also support the need for folic acid (found in spinach, orange juice and yeast), which is essential for brain function, and appears to reduce age-related cognitive decline and dementia. And BDNF, important for learning and memory as well as metabolic regulation (so there’s a connection there with obesity), is helped by omega-3 fatty acids and the curry spice curcumin, and also, it seems, smaller food portions.

[1293] Gómez-Pinilla, F.
(2008).  Brain foods: the effects of nutrients on brain function.
Nat Rev Neurosci. 9(7), 568 - 578.

Full text is available online at www.nature.com/nrn/journal/v9/n7/abs/nrn2421.html

Vitamin B12, folate, and cognitive function

Confirming earlier studies, a large epidemiological study has found that older people with normal vitamin B12 status and high levels of folate had higher scores on a test of cognitive function. The study clarifies some inconsistencies in earlier research by disentangling the interaction between these factors. It appears seniors with normal levels of vitamin B12 perform better if folate level is high, but when vitamin B12 is low, high levels of folate are associated with poor cognitive performance, as well as a greater probability of anemia. There are also indications that the combination might be a factor in some other diseases.

[1443] Morris, M S., Jacques P. F., Rosenberg I. H., & Selhub J.
(2007).  Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification.
Am J Clin Nutr. 85(1), 193 - 200.


Folic acid supplementation may improve cognitive performance

A study involving 818 older adults with raised homocysteine levels and normal vitamin B12 levels found that those given daily folic acid supplements (800 micrograms) for 3 years had lower homocysteine levels and improved cognitive performance compared to those given a placebo.

[443] Durga, J., van Boxtel M. P. J., Schouten E. G., Kok F. J., Jolles J., Katan M. B., et al.
(2007).  Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial.
Lancet. 369(9557), 208 - 216.


More evidence for value of folate for aging brains

Confirming a growing body of evidence, a study of 50-85 year old Boston-area men (members of the ongoing Normative Aging Study) found that men who obtained more folate in their diets showed significantly less of a decline in verbal fluency skills over the course of three years than did men with lower dietary folate intake. High folate levels also appeared protective against declines in spatial copying. The effects of folate were independent of its impact on homocysteine, which turned out to be more strongly associated with tests of memory. Folate is a B vitamin found particularly in leafy green vegetables and citrus fruit.

[888] Tucker, K. L., Qiao N., Scott T., Rosenberg I., & Spiro A.
(2005).  High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study.
Am J Clin Nutr. 82(3), 627 - 635.


Preventing high levels of homocysteine may protect against age-related cognitive impairment

Previous studies have found a link between high levels of homocysteine and poor cognitive performance, but it has been difficult to work out just what the association is, in view of confounding factors such as cardiovascular risk factors and levels of folate, B12, and B6, all of which play a role in high levels of homocysteine. A new analysis has disentangled these factors, and has found that, in people over 60 (but not those under 60), higher levels of homocysteine are independently associated with lower levels of cognitive performance. Similarly, higher levels of vitamin B12 are associated with higher levels of cognitive performance. The researchers suggest vitamins B12, B6, and folate taken before 60 could help protect against later cognitive impairment.

[839] Wolf, P. A., Elias M. F., Sullivan L. M., D'Agostino R. B., Elias P. K., Jacques P. F., et al.
(2005).  Homocysteine and Cognitive Performance in the Framingham Offspring Study: Age Is Important.
Am. J. Epidemiol.. 162(7), 644 - 653.


Folates more effective in limiting Alzheimer's disease risk than antioxidants, other nutrients

Analysis of data from the Baltimore Longitudinal Study of Aging has revealed that those with higher intake of folates, vitamin E and vitamin B6 had a lower risk of developing Alzheimer’s. When the three vitamins were analyzed together, only folates were associated with a significantly decreased risk. Those who had at least 400mcg of folates a day (the recommended daily allowance) had a 55% reduction in risk of developing Alzheimer’s. Unfortunately, most people who reached that level did so by taking supplements, suggesting the difficulty of doing so through diet alone. Folates are abundant in foods such as liver, kidneys, yeast, fruits (like bananas and oranges), leafy vegetables, whole-wheat bread, lima beans, eggs and milk; however, they are often destroyed by cooking or processing. No association was found between vitamin C, carotenoids (such as beta-carotene) or vitamin B-12 intake and decreased Alzheimer's risk.

Corrada, M.M., Kawas,C.H., Hallfrisch,J., Muller,D. & Brookmeyer,R. Reduced risk of Alzheimer’s disease with high folate intake: The Baltimore Longitudinal Study of Aging. Alzheimer’s & Dementia, 1 (1), 11-18.


Moderately high homocysteine linked to Alzheimer’s risk

A study of 83 Alzheimer’s patients, 78 patients with vascular dementia, 64 stroke patients, and 71 healthy controls, found that elevated levels of homocysteine were associated with a more than five-fold increase in the risk for stroke, a nearly five-fold risk for vascualr dementia, and almost triple the risk for Alzheimer's disease. High blood levels of homocysteine have been found to be associated with an increased heart attack risk in several studies. High levels of homocysteine have been found to be associated with deficiencies in vitamin B12 and folate, and also with smoking.

McIlroy, S.P., Dynan, K.B., Lawson, J.T., Patterson, C.C. & Passmore, A.P. 2002. Moderately Elevated Plasma Homocysteine, Methylenetetrahydrofolate Reductase Genotype, and Risk for Stroke, Vascular Dementia, and Alzheimer Disease in Northern Ireland. Stroke, 33, 2351 – 2356.


Study links high levels of homocysteine, and folic acid or vitamin B-12 deficiencies to cognitive decline

Current estimates suggest that more than one million elderly in Europe and about 750,000 elderly in North America become cognitively impaired each year. Recent research suggests that deficiencies of folate or vitamin B-12 and elevations of plasma homocysteine (tHcy) may be partly responsible. A British study of 331 participants in a longitudinal survey found significant negative effects on cognition in the elderly subjects who had deficiencies of folic acid or vitamin B-12 and elevated tHcy. In the older group (aged 76-78), increased levels of tHcy correlated both with lower serum folate and vitamin B-12 concentrations and with lower cognitive test scores. In the younger group (aged 61-63),higher folate concentrations correlated with higher scores on one of the assessment tests, but otherwise no effects of B vitamins or tHcy were apparent.
Green leafy vegetables, citrus fruits and juices, whole wheat bread and dry beans are good sources of folate.

[899] Duthie, S. J., Whalley L. J., Collins A. R., Leaper S., Berger K., & Deary I. J.
(2002).  Homocysteine, B vitamin status, and cognitive function in the elderly.
Am J Clin Nutr. 75(5), 908 - 913.

Smith, A.D. 2002. Homocysteine, B vitamins and cognitive deficit in the elderly. American Journal of Clinical Nutrition, 75,785-6.


Folic acid possibly a key factor in preventing Alzheimer's disease

Experiments with mice bred with mutant genes that cause Alzheimer's disease found that those mice fed on a diet deficient in folate had fewer neurons in the hippocampus ( a brain region critical for learning and memory that is destroyed as plaques accumulate during Alzheimer’s disease), and elevated levels of homocysteine. Researchers suspect that increased levels of homocysteine in the brain caused damage to the DNA of nerve cells in the hippocampus. In the mice fed an adequate amount of folate, nerve cells in this brain region were able to repair the damage. But in those mice fed a folate-deficient diet, nerve cells were unable to repair this damage. A human study is being planned.
Green leafy vegetables, citrus fruits and juices, whole wheat bread and dry beans are good sources of folate. In the U.S., since 1998, the Food and Drug Administration has required the addition of folic acid to enriched breads, cereals, flours, corn meals, pastas, rice, and other grain products.

Kruman, I.I., Kumaravel, T.S., Lohani, A., Pedersen, W.A., Cutler, R.G., Kruman, Y., Haughey, N., Lee, J., Evans, M. & Mattson, M.P. 2002. Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Them to Amyloid Toxicity in Experimental Models of Alzheimer's Disease. Journal of Neuroscience, 22, 1752-1762.


High homocysteine levels may double Alzheimer's risk

Findings from the long-running Framingham study found people with elevated levels of homocysteine in the blood had nearly double the risk of developing Alzheimer’s disease (AD). This study is the first to tie homocysteine levels measured several years before with later diagnosis of AD and other dementias, and provides the most powerful evidence yet of the link between high homocysteine levels and AD.

Seshadri, S., Beiser, A., Selhub, J., Jacques, P.F., Rosenberg, I.H., D'Agostino, R.B., Wilson, P.W.F. & Wolf, P.A. 2002. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. The New England Journal of Medicine, 346, 476-483.


Research ties vitamin B12 and folate deficiencies with Alzheimer's disease

People with low levels of B12 or folate may have a higher risk of developing Alzheimer's disease. A 3-year Swedish study of 370 people 75-years-old and older found that more than half (46 out of 78) of those diagnosed with dementia during the timeframe of the study had both low levels of vitamin B12 or folate and Alzheimer's type dementia. Low vitamin B12 and folate levels have long been observed in elderly people, and it has been theorized that this vitamin deficiency might be tied to neurological or psychiatric disorders. This study breaks new ground by connecting these deficiencies with Alzheimer's disease.
Vitamins B12 and folate (a form of water-soluble vitamin B) are found in common foods. Vitamin B12 is naturally found in animal foods including fish, milk and milk products, eggs, meat, and poultry. Leafy greens such as spinach and turnip greens, dry beans and peas, fortified cereals and grain products, and some fruits and vegetables are rich food sources of folate.

[2416] Wang, H. - X., Wahlin Å., Basun H., Fastbom J., Winblad B., & Fratiglioni L.
(2001).  Vitamin B12 and folate in relation to the development of Alzheimer’s disease.
Neurology. 56(9), 1188 - 1194.


High homocysteine levels are associated with decreased memory capability after age 60

Recent studies have linked Alzheimer disease and dementia after multiple strokes to extremely high serum homocysteine concentrations. A survey of 1299 men and women aged 60 and over, none of who had previously had a stroke, found an independent relationship between very high homocysteine levels and poor performance on cognitive tests. The folate status of the participants was checked as folate has been shown to significantly modify homocysteine levels. Story recall was worse among subjects with a combination of low folate and high homocysteine than in those whose homocysteine levels were normal or low. Homocysteine levels increased with age and were accompanied by a comparable decline in folate status. The researchers found independent associations between the highest levels of homocysteine and poorer recall. Among subjects with the highest level of homocysteine, the odds of passing a word delayed-recall test were identical whether their folate status was high or low.

[2415] Morris, M S., Jacques P. F., Rosenberg I. H., & Selhub J.
(2001).  Hyperhomocysteinemia associated with poor recall in the third National Health and Nutrition Examination Survey.
The American Journal of Clinical Nutrition. 73(5), 927 - 933.