Abstract: We included five trials with 879 participants which investigated B vitamin supplements. In four trials, the intervention was a combination of vitamins B6, B12, and folic acid; in one, it was folic acid only. Doses varied. We considered there to be some risks of performance and attrition bias and of selective outcome reporting among these trials. Our primary efficacy outcomes were the incidence of dementia and scores on measures of overall cognitive function. None of the trials reported the incidence of dementia and the evidence on overall cognitive function was of very low-quality. There was probably little or no effect of B vitamins taken for six to 24 months on episodic memory, executive function, speed of processing, or quality of life. The evidence on our other secondary clinical outcomes, including harms, was very sparse or very low-quality. There was evidence from one study that there may be a slower rate of brain atrophy over two years in participants taking B vitamins. The same study reported subgroup analyses based on the level of serum homocysteine (tHcy) at baseline and found evidence that B vitamins may improve episodic memory in those with tHcy above the median at baseline. We included one trial (n = 516) of vitamin E supplementation. Vitamin E was given as 1000 IU of alpha-tocopherol twice daily. We considered this trial to be at risk of attrition and selective reporting bias. There was probably no effect of vitamin E on the probability of progression from MCI to Alzheimer's dementia over three years (HR 1.02; 95% CI 0.74 to 1.41; n = 516; 1 study, moderate-quality evidence). There was also no evidence of an effect at intermediate time points. The available data did not allow us to conduct analyses, but the authors reported no significant effect of three years of supplementation with vitamin E on overall cognitive function, episodic memory, speed of processing, clinical global impression, functional performance, adverse events, or mortality (five deaths in each group). We considered this to be low-quality evidence. We included one trial (n = 256) of combined vitamin E and vitamin C supplementation and one trial (n = 26) of supplementation with chromium picolinate. In both cases, there was a single eligible cognitive outcome, but we considered the evidence to be very low-quality and so could not be sure of any effects. The evidence on vitamin and mineral supplements as treatments for MCI is very limited. Three years of treatment with high-dose vitamin E probably does not reduce the risk of progression to dementia, but we have no data on this outcome for other supplements. Only B vitamins have been assessed in more than one RCT. There is no evidence for beneficial effects on cognition of supplementation with B vitamins for six to 24 months. Evidence from a single study of a reduced rate of brain atrophy in participants taking vitamin B and a beneficial effect of vitamin B on episodic memory in those with higher tHcy at baseline warrants attempted replication.

Plain-language summary: We found eight randomised controlled trials (RCTs), which investigated four different types of vitamin or mineral pills by comparing them to a placebo (a dummy pill). The vitamins tested were B vitamins (vitamin B6, vitamin B12 and folic acid), vitamin E, and vitamin E and C given together. The only mineral tested was chromium. Vitamin B combination versus placebo Five trials with a total of 879 participants compared B vitamins with placebo. Four used combinations of vitamin B6, vitamin B12, and folic acid; one small study tested folic acid on its own. None of these studies reported whether or not participants developed dementia. These studies did not find that memory or thinking skills differed between the group of people who took vitamin B supplements and those who took placebo after treatment lasting six months to two years. Our confidence in the results on different tests used in the studies varied from moderate to very low. Two years of vitamin B supplements did seem to help memory in a small subgroup of participants in one study who could be identified by a particular blood test at the start of the trial. One study found that there was probably no effect on participants' quality of life. One study scanned the brains of some participants and reported that B vitamins may slow the rate of brain shrinkage. Harmful effects and deaths were reported in very few participants and we cannot conclude whether or not there are harms from taking these or similar combinations of B vitamins. Vitamin E versus placebo. One study with 516 participants compared a relatively high dose of vitamin E (2000 IU a day) to placebo in people who were also taking a multivitamin containing 15 IU of vitamin E (the daily requirement for vitamin E is approximately 30 IU). The risk of developing dementia due to Alzheimer’s disease (the commonest form of dementia) is probably not affected by three years of treatment with high-dose vitamin E. The quality of the evidence for other outcomes was lower, but there may also be no effect of this dose of vitamin E on specific memory or thinking skills or on how well people could manage their daily activities. Vitamin E and C versus placebo One study with 256 participants compared a combination of vitamins C and E with placebo. It found no effect on overall memory and thinking skills, but we had little confidence in this result because of the quality of the evidence. Chromium picolinate versus placebo Only one very small study with 26 participants investigated the effect of chromium supplements. This study was too small for us to be able to draw any conclusions. The amount and quality of research evidence about vitamin and mineral supplements for treating MCI in people without nutritional deficiency is limited. At the moment, it is not possible to identify any supplements which can reduce the risk of people with MCI developing dementia or which can effectively treat their symptoms. More research is needed before we can answer our review question.