B vitamins have ‘significantly favorable effects’ on cognitive scores in older people: RCTs

By Stephen Daniells

- Last updated on GMT

Brain functioning is known to naturally decline as we age, but mild cognitive impairment (MCI) is a warning sign of dementia. The new study suggests B vitamins may help, but only in the absence of aspirin     Image © coffeekai / Getty Images
Brain functioning is known to naturally decline as we age, but mild cognitive impairment (MCI) is a warning sign of dementia. The new study suggests B vitamins may help, but only in the absence of aspirin Image © coffeekai / Getty Images

Related tags B vitamins Homocysteine levels Cognitive function Cognitive decline Brain health

Older people with mild cognitive impairment experienced significant cognitive benefits from supplementation with B vitamins, but only in people not using aspirin, says a pooled analyses of two randomized placebo-controlled trials.

Data published in the Journal of Nutrition, Health & Aging​ indicated that supplementation with vitamin B12, folic acid, with or without vitamin B6, led to significant reductions in the rate of cell loss in the brain (brain atrophy), compared to placebo, in older people with mild cognitive impairment (MCI).

When researchers from the Chinese University of Hong Kong and Oxford University divided the participants according to whether they were using aspirin, the data revealed that B vitamin supplementation led to significantly better scores on the Clinical Dementia Rating scale for non-aspirin users versus aspirin users.

The study used data from the VITACOG trial in the UK and a similar trial in Hong Kong, which the researchers refer to as the HK trial.

“Our pooled analysis suggested a significant drug-nutrient interaction between aspirin and B vitamins in older people with MCI,” ​they wrote. “B vitamins improved global cognitive functioning and slowed brain atrophy significantly in those not taking aspirin, but not in aspirin users. The negative interaction is most likely to lie between aspirin and folic acid.”


Brain functioning is known to naturally decline as we age, and mild cognitive impairment (MCI) is a transitional state when small changes in memory and other mental abilities coexist with normal functioning.

Such declines in functions are often a warning sign of dementia – a term used to describe various brain disorders that have a progressive loss of brain functioning in common.

The relationship between B vitamins and cognitive function has been postulated for many years and is linked to levels of the amino acid homocysteine. Researchers hypothesize that increased concentrations of the amino acid are connected to a higher rate of wasting in the brain, or atrophy, and therefore mild cognitive impairment (MCI).

The link is backed up by epidemiological studies that have reported an association between high levels of homocysteine and suspected or confirmed dementia. Indeed, the Framingham study reported that people with homocysteine levels above 14 micromoles per liter of serum had twice the risk of dementia.

Since tissue and plasma concentrations of homocysteine are determined by vitamin B status, as they are cofactors for enzymes involved in homocysteine metabolism, many different studies have examined if supplementation with B vitamins can impact measures of cognitive function and brain health in older adults. These studies have yielded conflicting, and often disappointing results.

The VITACOG trial is one of the studies to have yielded positive results, with data published in 2015 showing that high-dose B vitamin supplementation slowed brain wasting (atrophy) in people with MCI by 40% but only when omega-3 levels were already high.

Another finding from the original VITACOG data was that aspirin could exert a borderline negative effect on the potential benefits of B vitamin supplementation, a result also reported in the HK trial. Since the trials employed a similar design, the researchers decided to pool the data to explore these interactions in more detail.

Study detail

Data from 545 older people with MCI from both studies was analyzed, with the data showing that B vitamins significantly reduced brain atrophy in the overall study population (including aspirin users and non-users), but no effects on Clinical Dementia Rating (CDR) scores were detected. When they stratified the data between aspirin users and non-users they did observe a significant improvement in CDR scores for B vitamins but only in the non-users of aspirin.

On the other hand, no benefits were observed for measures of memory or executive function, said the researchers.

Commenting on the results, the researchers point the finger squarely at the interaction between aspirin and folic acid, with evidence from the scientific literature showing that aspirin may have “anti-folate effects”. The drug has been reported to increase some folate excretion in the urine. There are also reports that aspirin may inhibit the activity of an enzyme called folate-dependent dihydrofolate reductase (DHFR) in the liver, which means folic acid is not metabolized efficiently, leading to an increase in circulating levels of unmetabolized folic acid, which may be detrimental.

To conclude, the researchers called for, “Further investigations on the mechanisms underlying this interaction may lead to more effective use of B vitamins in the prevention of dementia.”

Source: Journal of Nutrition, Health & Aging
2021; Volume 25, Issue 10, Pages 1154-1160. doi: 10.1007/s12603-021-1708-1
“Effectiveness of B Vitamins and Their Interactions with Aspirin in Improving Cognitive Functioning in Older People with Mild Cognitive Impairment: Pooled Post-Hoc Analyses of Two Randomized Trials”
Authors: Y. Wu et al.

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