Therese Pei Fong Chow Research Centre for Prevention of Dementia, the Chinese University of Hong Kong, discuss if B vitamins can improve cognitive function in older people
With increasing age, more and more older people develop some degree of cognitive impairment, especially in short term memory and problemsolving ability. This is now recognised as a clinical syndrome of mild cognitive impairment (MCI), caused by degeneration of neuronal cells and small blood vessels in the brain. Apart from some functional limitations from cognitive impairment, people with MCI are higher risk of developing dementia. (Livingston et al. 2017) So far there is no established effective treatment for MCI, though the combination of physical exercise, healthy diet and cognitive training have been shown to improve cognitive function significantly in older people at risk of cognitive impairment. (Ngandu et al. 2015)
Many people with MCI have elevated homocysteine concentration in the blood. Homocysteine is a well-recognised vascular risk factor. Apart from that, it is associated with Alzheimer’s disease and strokes. Experiments in animal and cell models have shown that excess homocysteine is neurotoxic. In addition, homocysteine impairs synthesis of neurotransmitters and myelin sheath around axons of neurons, which will impair the ability of neurons to transmit signals among themselves effectively. (Tucker et al. 2005)
The potential of B vitamins?
Homocysteine is a by-product of a non-essential amino acid, methionine. Its metabolism is dependent on the availability of folate, vitamin B12 and vitamin B6, in descending order of importance. As expected, these vitamin supplements can lower homocysteine concentration in blood by as much as one third. It is therefore plausible that B vitamins may improve cognitive function in older people with MCI. This is an important research question for public health as B vitamins may be an effective and relatively safe means to prevent dementia in older people.
Randomised trials of B vitamins have been performed in older people with or without cognitive impairment. But the results have been mixed. Our research group was particularly impressed by the VITACOG trial in Oxford, UK, which showed that the combination of vitamin B12, folic acid and vitamin B6 could significantly reduce the rate of the shrinkage of the brain on serial MRI scans over 18 months in older people with MCI. (Smith et. al 2010) Interestingly, the effect was only evident in those with mildly elevated plasma homocysteine (≥ 11 μmol/L) and in those with relatively high plasma omega 3 concentrations, suggesting that not everyone may benefit from B vitamins.
We have performed a similar but larger randomised placebo-controlled trial in 279 older Chinese people with MCI, with the aim to demonstrate the effectiveness of B vitamins to improve their cognitive function over two years. (Kwok et al. 2019) We chose to use a lower dose of folic acid (400 mcg as opposed to 800 mcg in the VITACOG trial) because there is some evidence to suggest that higher doses of folic acid may promote existing cancers. We also did not use vitamin B6 which has minor homocysteine lowering effect. The trial subjects were selected for mildly elevated serum homocysteine (≥ 10 μmol/L).
Our trial showed that the B vitamins were effective in lowering homocysteine concentration in the blood, but they were not effective in improving cognitive function in older people with MCI overall. There was a significant reduction in depressive symptoms at month 12, but this was not sustained at month 24. The latter finding is consistent with other trials which showed a therapeutic effect of higher doses of folic acid (2 mg daily) in depression. (Coppen et al. 2005) We were the first to demonstrate that this effect of folic acid may not be sustained after a year.
Negative impacts of aspirin?
Apart from this, we found an interesting negative interaction effect of aspirin on the cognitive effect of B vitamins. In other words, we found that among older people who were taking aspirin, presumably for vascular diseases, had more cognitive decline with B vitamins than those who took placebo tablets. The VITACOG trial had similar finding in that the aspirin users did not benefit from B vitamins in terms of brain atrophy.
This finding is important because aspirin is a common drug among older people. Our results suggested that those people who take aspirin regularly should not be taking folic acid. The reason why we think aspirin is interacting with folic acid rather than vitamin B12 is that in our other trial of vitamin B12 alone, there was no significant interaction between aspirin use and vitamin B12 in cognitive outcomes. (Kwok et al. 2017)
Folic acid is a synthetic form of folate, which requires slow conversion into active forms of folate primarily in the liver. It is possible that aspirin may be interfering with this conversion process, and this may lead to an increase in circulating level of unmetabolised folic acid (UMF). There have been public health concerns about UMF as some countries fortify the flour with folic acid to prevent neural tube defects in newborn babies, and folic acid is commonly added in breakfast cereals. The worry is over the potential of UMF to promote the growth of existing cancers, though this has not been proven. The effect of UMF on brain health has not been examined in any detail, but there is experimental evidence that excessive UMF impairs neurodevelopment of neonates. (Wien and Desoto 2017)
Although our trial failed to demonstrate the effect of B vitamins in improving cognitive function in older people with MCI, we have under-covered a potentially important drug nutrient interaction. Further research into the mechanisms of this interaction may shed light on how B vitamins can promote brain health, and point to the groups of people who are more likely to respond to B vitamins in cognitive function.
This study was supported by the General Research Grant from the Hong Kong Research Grant Council (Ref no. 466612).
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