Leading Edge

http://neurology.thelancet.com Vol 6 March 2007 199

Folic acid: a supplementary questionThe results of a randomised clinical trial, published in The Lancet in January 2007, provide intriguing evidence that folic acid supplementation can help to ward off the seemingly inescapable cognitive decline that accompanies advancing age. Individuals from ages 50–70 years who received folic acid supplementation over the course of 3 years did signifi cantly better on measures of memory, information processing speed, and sensorimotor speed than those taking placebo. On the surface, this seems like encouraging news for our growing ageing population, and adds to the evidence that an increased dietary intake of folic acid would be benefi cial. But should we advocate folic acid supplementation—or even fortifi cation—given that our knowledge of the potential adverse consequences on many aspects of health and in much of the population remains scarce?

Since 1998, fl our and other grain products in the USA have been fortifi ed with folic acid, and many other countries, including Canada, much of South America, some Middle Eastern countries, and Indonesia, have followed suit. Although no European or Australasian countries have so far introduced fortifi cation, there is ongoing debate, and in December 2006, the UK Food Standards Agency launched a consultation process to reconsider mandatory fortifi cation versus alternative options to increase folate intake. The aim of fortifi cation is to reduce the incidence of neural tube defects, and epidemiological studies in countries that have mandated fortifi cation suggest that this has been a successful endeavour. However, fortifi cation exposes many sections of the population beyond the original target group, women of childbearing age, to high levels of folic acid.

Critics of fortifi cation argue that increased folic acid levels might mask or even exacerbate defi ciencies in vitamin B12. Such defi ciencies are most prevalent in the elderly as our capacity to absorb B12 declines with age, making this section of the population particularly vulnerable to the adverse eff ects of increases in folic acid. Anaemia is a common symptom of vitamin B12 defi ciency, and if untreated, can result in irreversible nerve damage. Some disturbing consequences of the interaction between folate and vitamin B12 for cognitive function have also been reported. Studies have shown that cognitive function declines steeply in individuals who have a high folate status and low levels of vitamin

B12, whereas those with normal levels of vitamin B12 are protected against cognitive decline. Importantly, individuals with a vitamin B12 defi ciency were excluded from the study reported in The Lancet. Moreover, the study participants had high baseline plasma total homocysteine levels, indicative of low folate status, and so these fi ndings cannot be generalised to other sections of the population.

Increasing dietary intake of folic acid raises further causes for concern. It had been hoped that the introduction of folic acid fortifi cation would help to reduce the incidence of cardiovascular disease and stroke through a reduction in homocysteine levels, but this initial optimism has been dampened with some trials showing only a minimal eff ect or no eff ect at all. Nevertheless, studies are ongoing and there are some indications that we should remain hopeful. Epidemiological studies generally indicate that folate has a protective eff ect against some types of cancer. However, there are some suggestions that high levels of folic acid increase the risk of breast cancer and accelerate tumour growth in colorectal cancer. Recently, it has been reported that high levels of unmetabolised folic acid were linked to impaired immune function in women aged 60 and over.

Studies of the consequences—both negative and positive—of folic acid supplementation and fortifi cation remain to be validated with long-term, large-scale clinical trials that shed light on the eff ects on multiple health outcomes. It would be important to understand the infl uences of potential sources of variation in response to folic acid, such as age, vitamin status, genetic factors, medical conditions, and drugs. A greater appreciation of the interactions between folate and vitamin B12, disruptions to this tight partnership, and the underlying cause of the harmful events (unmetabolised folic acid, for example) could point us towards further causes for concern that require investigation. The potentially adverse consequences of increased folic acid intake give us reason to be cautious about uncontrolled population-wide interventions. Moreover, recent studies of women of child-bearing age in the USA have found reduced blood levels of folates, despite the fortifi cation programme, emphasising the need for additional or alternative solutions. Instead, we should step up our eff orts to encourage targeted supplementation and promote healthy diets that are rich in a variety of folates, and not just folic acid, in those groups who would benefi t most. ■ The Lancet Neurology

For The Lancet trial see Lancet 2007; 369: 208–16

For details of this research see Arch Neurol 2005; 62: 641–45 and Am J Clin Nutr 2007; 85: 193–200