No evidence that folic acid with or without vitamin B12 improves cognitive function of unselected elderly people with or without dementia. Long-term supplementation may benefit cognitive function of healthy older people with high homocysteine levels

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 people 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. Eight trials met the criteria for inclusion. It was not possible to pool the data because the trials studied different populations, tested folic acid in different doses, and used different outcome measures. There were two trials of folic acid in conjunction with B12. The analysis showed significant benefit of folic acid over placebo in some measures of cognition in a long-term trial recruiting elderly people with high homocysteine levels from a general population. In one pilot trial, 1 mg/day of folic acid was associated with significant improvement in behavioural response to cholinesterase inhibitors in people with Alzheimer's disease.

Authors' conclusions: 

The small number of studies which have been done provide no consistent evidence either way that folic acid, with or without vitamin B12, has a beneficial effect on cognitive function of unselected healthy or cognitively impaired older people. In a preliminary study, folic acid was associated with improvement in the response of people with Alzheimer's disease to cholinesterase inhibitors. In another, long-term use appeared to improve the cognitive function of healthy older people with high homocysteine levels.  More studies are needed on this important issue.

Read the full abstract...

Folate deficiency can result in congenital neural tube defects and megaloblastic anaemia. Low folate levels may be due to insufficient dietary intake or inefficient absorption, but impaired metabolic utilization also occurs.

Because B12 deficiency can produce a similar anaemia to folate deficiency, there is a risk that folate supplementation can delay the diagnosis of B12 deficiency, which can cause irreversible neurological damage.  Folic acid supplements may sometimes therefore include vitamin B12 supplements with simultaneous administration of vitamin B12.

Lesser degrees of folate inadequacy are associated with high blood levels of the amino acid homocysteine which has been linked with the risk of arterial disease, dementia and Alzheimer's disease. There is therefore interest in whether dietary supplementation can improve cognitive function in the elderly.

However, any apparent benefit from folic acid which was given in combination with B12 needs to be "corrected" for any effect of vitamin B12 alone. A separate Cochrane review of vitamin B12 and cognitive function has therefore been published.


To examine the effects of folic acid supplementation, with or without vitamin B12, on elderly healthy or 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 10 October 2007 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, EMBASE, CINAHL, PsychINFO and LILACS were searched (years 2003-2007) 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: 

Eight randomized controlled trials fulfilled the inclusion criteria for this review. Four trials enrolled healthy older people, and four recruited participants with mild to moderate cognitive impairment or dementia with or without diagnosed folate deficiency. Pooling the data was not possible owing to heterogeneity in sample selections, outcomes, trial duration, and dosage. Two studies involved a combination of folic acid and vitamin B12.

There is no adequate evidence of benefit from folic acid supplemententation with or without vitamin B12 on cognitive function and mood of unselected healthy elderly people. However, in one trial enrolling a selected group of healthy elderly people with high homocysteine levels, 800 mcg/day folic acid supplementation over three years was associated with significant benefit in terms of global functioning (WMD 0.05, 95% CI 0.004 to 0.096, P = 0.033); memory storage (WMD 0.14, 95% CI 0.04 to 0.24, P = 0.006) and information-processing speed (WMD 0.09, 95% CI 0.02 to 0.16, P = 0.016).

Four trials involved people with cognitive impairment. In one pilot trial enrolling people with Alzheimer's disease, the overall response to cholinesterase inhibitors significantly improved with folic acid at a dose of 1mg/day (odds ratio: 4.06, 95% CI 1.22 to 13.53; P = 0.02) and there was a significant improvement in scores on the Instrumental Activities of Daily Living and the Social Behaviour subscale of the Nurse's Observation Scale for Geriatric Patients (WMD 4.01, 95% CI 0.50 to 7.52, P = 0.02). Other trials involving people with cognitive impairment did not show any benefit in measures of cognitive function from folic acid, with or without vitamin B12.

Folic acid plus vitamin B12 was effective in reducing serum homocysteine concentrations (WMD -5.90, 95% CI -8.43 to -3.37, P < 0.00001). Folic acid was well tolerated and no adverse effects were reported.