Null Series: B vitamins for preventing mental decline as we age

Remember that mischievous little African bee and the epidemiological study that recently claimed to show that low vitamin B₁₂ levels were associated with brain atrophy? As we uncovered, the study had actually found no tenable correlations between the B vitamin and brain size, and the Oxford authors were unable to give a biologically plausible explanation for how vitamin B₁₂ levels might facilitate brain atrophy. Even so, they had concluded that a randomized clinical trial of high dose vitamin B₁₂ supplementation was needed to see if the vitamin could help prevent cognitive impairment among elderly.

We didn’t have to wait long. The results of the VITAL - VITamins to slow ALzheimer's disease (Homocysteine Study) were recently published in the Journal of the American Medical Association.

This was a randomized, double-blind, placebo-controlled clinical trial conducted under the Alzheimer Disease Cooperative Study, a consortium of 40 medical centers funded by the National Institute on Aging. [Clinicaltrials.gov ID: NCT00056225] For this phase III clinical trial, Alzheimer patients, average age 76 and just over half women, were recruited and then screened to confirm their diagnoses of mild to moderate Alzheimer’s disease. To participate, the patients also had to have stable medical conditions and caretaker situations; and no mental retardation, vitamin B₁₂ or folate deficiency, kidney problems, cancers, or sensory impairment or other disability that would prohibit participation, and not already be taking supplements. They also had to have no history of strokes or epilepsy, focal brain lesions, head injury with loss of consciousness, any major psychiatric disorder, or substance abuse that could confound the results.

A total of 409 patients were randomly assigned to two groups: 240 were given high-dose vitamin B supplements [5 mg/day folate, 25 mg/day vitamin B₆, and 1 mg/day vitamin B₁₂] and 169 were given a placebo. They were closely followed with clinical exams every 3 months for 18 months from February 20, 2003, to December 15, 2006. At each exam, they had vital signs and physical examinations; urine and blood tests; and cognition and behavioral assessments. A total of 84% and 82% participants, respectively, completed the trial, fully complying with taking their study pills.

The primary outcome was any change in their cognitive scores on the Alzheimer Disease Assessment Scale (ADAS-cog), a 70-point test which evaluates memory, attention, language, orientation and praxis. A higher score equates with greater cognitive impairment. The investigators also followed their Mini-mental State Examination (MMSE) scores, activities of daily living, neuropsychiatric inventory, Alzheimer quality of life assessments, and deaths.

At the beginning of the trial, participants had similar homocysteine levels and vitamin B12 and B6 levels. Over the 18 months, the mean homocysteine levels in the intervention group dropped significantly, while remaining stable in the control group:

But, it didn’t matter. There was no difference between the intervention and control groups in the loss of cognitive function:

Neither the vitamins, nor changes in homocysteine levels, had any effect on slowing cognitive decline among the Alzheimer’s patients. The B vitamins didn’t help to preserve or improve their cognitive function. Both groups also had nearly identical declines in clinical dementia ratings, activities of daily living and quality of life measures, and MMSE scores. The authors did a secondary analyses on subgroups based on homocysteine levels and on a subgroup with the apolipoprotein-4 genotype and the results were unchanged.

While adverse effects were low, an average of 9.8% of the seniors on the vitamins experienced each of the ten reported side effects, compared to 5.8% of the placebo group. The adverse events, while only marginally statistically significant, were all higher among those taking vitamins: depression (seen in 27.9% of intervention group compared to 17.8% of placebo), restlessness, hyperhidrosis, headache, arthralgia, dyspnea, joint swelling, respiratory infections, urinary tract infections and blurred vision. The authors commented that these results raise a potential safety issue in vitamin B supplementation.

Finally, there was no difference in survival rates between the vitamin and placebo groups:

This was a null study.

High doses of vitamins B₁₂ and B₆ had no effect on cognitive function or clinical outcomes for people with age-related Alzheimer’s who don’t have B vitamin deficiency.

Background information on the evidence on vitamin B₁₂

Vitamin B₁₂ is an essential vitamin that plays a role in maintaining healthy nerve cells and red blood cells. It’s also called cobalamine because it contains the metal cobalt. Vitamin B₁₂ is found naturally in animal foods, such as beef, pork, eggs, chicken; and fish; and is in fortified breakfast cereals (the main source for vegetarians).

Most children and adults in the United States get the recommended amounts in their regular diets, according to the National Health and Nutrition Examination Survey (NHANES III-1988-94) and the Continuing Survey of Food Intakes by Individuals (CSFII 1994-96). According to the National Academy of Science, Food and Nutrition Board, the Recommended Dietary Allowance for adults is 2.4mcg/day and the median intake among adults in the U.S. is 5mcg/day for men and 3.5mcg/day for women, with intakes in the highest percentiles more than ten times the RDA.

While deficiencies are not common, when they do occur, they’re most likely to be when the body is unable to absorb the vitamin from foods. Anything that reduces the stomach juices, hydrochloric acid, can lead to deficiencies because those stomach acids release the vitamin from the protein in foods so that it can be absorbed in the intestines. People with a stomach or intestinal disorder, such as atrophic gastritis (inflammation and growth of intestinal bacteria); pernicious anemia patients; those who’ve had stomach or intestinal surgery, such as bariatrics; and people on certain medications (such as metformin for diabetes, and meds for GERD and peptic ulcers) may develop deficiencies. According to the National Academy of Science, 10% to 30% of older people can develop atrophic gastritis, but they can absorb vitamin B₁₂ from vitamin pills, since in this form, the vitamin is already bioavailable.

Strict vegetarians who avoid animal foods are also at special risk of deficiencies (and the vitamin isn’t always added to nutritional yeasts, as is popularly believed). Chronic dieters can also increase their risks. Deficiencies are rare in babies, but can occur within months of birth in those whose mothers are deficient, most common with breastfed babies of mothers who are strict vegetarians. Vitamin B₁₂ in infants can result in permanent neurological damage which is why vegetarian mothers are especially advised to consult a pediatrician and their obstetrician about appropriate supplements.

The symptoms associated with vitamin B₁₂ deficiency can include subtly reduced cognitive function and advance all the way to anemia and dementia. They can involve weakness and fatigue, constipation, loss of appetite, weight loss, numbness and tingling of hands and feet, balance problems, depression, confusion, and soreness of the mouth and tongue; and failure to thrive and delayed development in babies. Deficiencies are treated with vitamin B₁₂. (Folic acid can correct the anemia, but not the nerve damage from vitamin B₁₂ deficiency and can lead to permanent nerve damage if not appropriately treated).

But because vitamin B₁₂ can be a treatment for memory problems and dementia seen in deficiencies that doesn’t mean that it can treat or prevent cognitive decline and dementia in those without deficiencies. Beyond helping deficiencies, no clinical evidence to date has supported any ability of extra vitamin B₁₂ for preventing dementia and cognitive decline, nor has it ever been shown that extra B vitamins will improve mental sharpness, mood or intellect.

Water soluble vitamins don’t work that way. After our body uses what it needs, the rest mostly goes to tint our pee.

Deficiencies of Vitamin B₁₂, folate, and vitamin B₆ can increase homocysteine levels. Homocysteine levels also correlate with aging and, hence, higher levels are associated among those with age-related dementia. This correlation was the source of the homocysteine theory for its possible role in age-related conditions. And clinical trials to test this observed correlation ensued. They've all been null studies.

There were three Cochrane systematic reviews of the randomized clinical trials of folic acid, vitamin B₆ and vitamin B₁₂ for cognitive function published in 2003 by the Cochrane Dementia and Cognitive Improvement Group in Oxford, UK. None of the reviews found evidence of improvement in cognition or dementia among any of the populations studied or various vitamin doses, although most of the studies were small. Among the vitamin B₆ studies, two had evaluated vitamin B₆ among healthy seniors, with and without vitamin B₆ deficiency, and found no beneficial effects of supplements on mental function or depression. The Cochrane review of vitamin B₁₂ supplementation trials conducted on people with cognitive impairment or dementia and low levels of B₁₂ found no statistical effect on vitamin B₁₂ supplements on cognition, even among these seniors with low B₁₂ levels. And the Cochrane review of clinical trials of supplements of folic acid, with or without vitamin B_12, included studies on healthy elderly and those with mild to moderate cognitive impairment or dementia, with and without vitamin deficiencies. The reviewers found no beneficial effects of either vitamin on cognitive decline, mood or dementia.

The pilot study behind this new phase III trial by the Vital Trial Collaborative Group had also been published in 2003, in the Journal of Internal Medicine. Recruiting from both the community and doctors offices, 174 participants, average age of 75, who met the study criteria attended an initial screening exam and had their medical histories taken; their cognitive functions assessed using the Mini-mental State Examination (MMSE) and the cognitive section of the Alzheimer’s Disease Assessment Scale (ADAS-Cog); and their activities of daily living assessed using the Bristol Activities of Daily Living Scale. Their blood and urine was collected for laboratory tests (homocysteine, vitamin levels and other biochemical markers). After a run-in trial, 140 were randomized to receive either low-dose aspirin (81 mg) or a placebo; and 2 mg folic acid plus 1 mg vitamin B₁₂ or a placebo; and 500 mg vitamins E plus 200 mg vitamin C or a placebo.

At the start of the trial, baseline B₁₂ blood levels among the study participants were unrelated to their ADAS-Cognitive scores or MMSE scores. Vitamin B₁₂ levels were inversely related to homocysteine levels, as predicted, and homocysteine levels were associated with age.

After 18 months, 129 participants completed the trial and their cognitive tests and activities of daily living scores were found to be unchanged by any of the treatment vitamins. The authors concluded:

None of the measures of cognitive function were materially altered by any of the treatments, which is to be expected given the size and duration of the pilot study… Long-term trials involving a much larger number of people at high-risk of dementia are now required…

And so began the long-term VITAL trial of high doses of B vitamins just found to be null, too. It would be safe to conclude that there is no evidence to date to support claims that B vitamins can help prevent age-related loss of cognition or Alzheimer's disease.

© 2008 Sandy Szwarc