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Folic acid with or without vitamin B12 for cognition and dementia

  • Review
  • Intervention

Authors

  • R Malouf,

  • J Grimley Evans,

  • A Areosa Sastre


Dr Reem Malouf, 256 Iffley Road, Oxford, UK. reemmalouf@yahoo.com.

Abstract

Background

Folates are vitamins essential to the development of the central nervous system. Insufficient folate activity at the time of conception and early pregnancy can result in congenital neural tube defects. In adult life folate deficiency has been known for decades to produce a characteristic form of anaemia ("megaloblastic"). More recently degrees of folate inadequacy, not severe enough to produce anaemia, have been found to be associated with high blood levels of the amino acid homocysteine. Elevated blood levels of homocysteine have been linked with the risk of arterial disease, dementia and Alzheimer's disease. Such degrees of folate inadequacy can arise because of insufficient folates in the diet or because of inefficient absorption or metabolic utilization of folates due to genetic variations. Conventional criteria for diagnosing folate deficiency may be inadequate for identifying people capable of benefiting from dietary supplementation. There is therefore interest in whether dietary supplements of folic acid (an artificial chemical analogue of naturally occurring folates) can improve cognitive function of people at risk of cognitive decline associated with ageing or dementia, whether by affecting homocysteine metabolism or through other mechanisms.

There is a risk that if folic acid is given to people who have undiagnosed deficiency of vitamin B12 it may lead to neurological damage. Vitamin B12 deficiency produces an anaemia identical to that of folate deficiency but also causes irreversible damage to the central and peripheral nervous systems. Folic acid will correct the anaemia of vitamin B12 deficiency and so delay diagnosis but will not prevent progression to neurological damage. For this reason trials of folic acid supplements may involve simultaneous administration of vitamin B12. Apparent benefit from folic acid given in the combination would therefore need to be "corrected" for any effect of vitamin B12 alone. A separate Cochrane review of vitamin B12 and cognitive function has been published (Malouf 2003).

Objectives

To examine the effects of folic acid supplementation, with or without vitamin B12, on elderly healthy and demented people, in preventing cognitive impairment or retarding its progress.

Search strategy

Trials were identified from a search of the Cochrane Dementia and Cognitive Improvement Group's Specialized Register on 9 April 2003 using the terms: folic acid, folate, vitamin B9, leucovorin, methyltetrahydrofolate, vitamin B12, cobalamin and cyanocobalamin. This Register contains references from all major health care databases and many ongoing trials databases. In addition MEDLINE and EMBASE (both all years) were searched for additional trials of folate with or without Vitamin B12 on healthy elderly people.

Selection criteria

All double-blind placebo-controlled randomized trials, in which supplements of folic acid with or without vitamin B12 were compared with placebo for elderly healthy people or people with any type of dementia or cognitive impairment.

Data collection and analysis

The reviewers independently applied the selection criteria and assessed study quality. One reviewer extracted and analysed the data. In comparing intervention with placebo, weighted mean differences and standardized mean difference or odds ratios were estimated.

Main results

Four randomized controlled trials fulfilled the inclusion criteria for this review. One trial (Bryan 2002) enrolled healthy women, and three (Fioravanti 1997; Sommer 1998; VITAL 2003) recruited people with mild to moderate cognitive impairment or dementia with or without diagnosed folate deficiency. Fioravanti 1997 enrolled people with mild to moderate cognitive impairment or dementia as judged by scores on the Mini-Mental State Examination (MMSE) and Global Deterioration Scale and with serum folate level <3ng/l. One trial (VITAL 2003) studied the effects of a combination of vitamin B12 and folic acid on patients with mild to moderate cognitive impairment due to Alzheimer's disease or mixed dementia.

Analysis of the included trials found no benefit from folic acid with or without vitamin B12 in comparison with placebo on any measures of cognition or mood for healthy or cognitively impaired or demented people.

Folic acid plus vitamin B12 was effective in reducing serum homocysteine concentrations. Folic acid was well tolerated and no adverse effects were reported.

Authors' conclusions

The available studies are limited in size and scope but provide no evidence that folic acid, with or without vitamin B12, has a beneficial effect on cognitive function or mood of health or cognitively impaired older people. The issue is important and more studies are needed.

Plain language summary

Plain language summary

No evidence that folic acid with or without vitamin B12 improves cognitive function of elderly healthy people or people with dementia.

In the economically developed world folate deficiency is one of the commonest vitamin deficiencies. Several reports suggest a higher prevalence of various psychiatric disorders in elderly patients with folate deficiency. There is interest in whether dietary supplements of folic acid (an artificial chemical analogue of naturally occurring folates) can improve cognitive function of people at risk of cognitive decline associated with ageing or dementia, whether by affecting homocysteine metabolism or through other mechanisms. Four trials met the criteria for inclusion and three provided enough data for analysing. It was not possible to pool the data because the trials studied different populations and tested folic acid in different doses, and in one trial in conjunction with B12. The analysis showed no significant beneficial effect of folic acid, with or without vitamin B12, over placebo on any measure of cognition or mood in healthy, cognitively impaired, or demented older people.

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