The Lancet Commission report is an heroic achievement but it was rather selective in the risk factors that it reported and which formed the basis of the widely-cited claim that more than a third of dementia cases might be prevented if all the modifiable risk factors could be tackled. The Commission omitted to mention raised plasma homocysteine. This risk factor has been identified in many studies, as recently reviewed (McCaddon & Miller, 2015; Smith & Refsum, 2016). For example, a meta-analysis from NIA considered raised homocysteine to be one of the three strongest risk factors, along with low education and decreased physical activity, and estimated that it has a relative risk of 1.93 and a Population Attributable Risk (PAR) of 21.7% (Beydoun et al., 2014). In view of this high PAR, it is therefore likely that if plasma homocysteine could be lowered it would have a significant impact upon dementia incidence. In fact, lowering of homocysteine (by about 30%) is readily achieved by treatment with high doses of B vitamins. Two trials have shown that lowering homocysteine reduces age-related cognitive decline in normal ageing (Durga et al., 2007) and slows both brain atrophy and cognitive decline in people with MCI (VITACOG trial) (de Jager et al., 2012; Douaud et al., 2013; Smith et al., 2010). The effect of B vitamin treatment on people with MCI who have high baseline homocysteine is consistent with a disease-modifying effect (Smith & Refsum, 2017) but trials are needed to demonstrate that this treatment will slow conversion from MCI to dementia.
The Lancet Commission’s omission of high homocysteine as a modifiable risk factor is unfortunate since the treatment (B vitamins) is safe and inexpensive and could significantly benefit people with MCI and would be highly cost-effective (Tsiachristas & Smith, 2016). It was also unfortunate that the Commissions incorrectly reported a paper from the VITACOG trial (de Jager et al., 2012) as showing a lack of effect of B vitamins on global cognition whereas in fact the paper showed a significant slowing of decline in MMSE in those with high homocysteine who were treated with B vitamins.
References
Beydoun, M. A., Beydoun, H. A., Gamaldo, A. A., Teel, A., Zonderman, A. B., & Wang, Y. (2014). Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health, 14(1), 643. doi:10.1186/1471-2458-14-643
de Jager, C. A., Oulhaj, A., Jacoby, R., Refsum, H., & Smith, A. D. (2012). Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. Int J Geriatr Psychiatry, 27(6), 592-600. doi:10.1002/gps.2758
Douaud, G., Refsum, H., de Jager, C. A., Jacoby, R., Nichols, T. E., Smith, S. M., & Smith, A. D. (2013). Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A, 110(23), 9523-9528. doi:10.1073/pnas.1301816110
Durga, J., van Boxtel, M. P., Schouten, E. G., Kok, F. J., Jolles, J., Katan, M. B., & Verhoef, P. (2007). Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet, 369(9557), 208-216.
McCaddon, A., & Miller, J. W. (2015). Assessing the association between homocysteine and cognition: reflections on Bradford Hill, meta-analyses and causality. Nutr Rev, 73(10), 723-735.
Smith, A. D., & Refsum, H. (2016). Homocysteine, B vitamins, and cognitive impairment. Annu Rev Nutr, 36, 211-239. doi:10.1146/annurev-nutr-071715-050947
Smith, A. D., & Refsum, H. (2017). Dementia prevention by disease-modification through nutrition. J Prev Alz Dis, in press. doi:http://dx.doi.org/10.14283/jpad.2017.16
Smith, A. D., Smith, S. M., de Jager, C. A., Whitbread, P., Johnston, C., Agacinski, G., . . . Refsum, H. (2010). Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment. A randomized controlled trial. PLoS ONE, 5(9), e12244. doi:10.1371/journal.pone.0012244.
Tsiachristas, A., & Smith, A. D. (2016). B-vitamins are potentially a cost-effective population health strategy to tackle dementia: Too good to be true? Alzheimers Dement (NY), 2, 156-161.
Comments
University of Oxford
The Lancet Commission report is an heroic achievement but it was rather selective in the risk factors that it reported and which formed the basis of the widely-cited claim that more than a third of dementia cases might be prevented if all the modifiable risk factors could be tackled. The Commission omitted to mention raised plasma homocysteine. This risk factor has been identified in many studies, as recently reviewed (McCaddon & Miller, 2015; Smith & Refsum, 2016). For example, a meta-analysis from NIA considered raised homocysteine to be one of the three strongest risk factors, along with low education and decreased physical activity, and estimated that it has a relative risk of 1.93 and a Population Attributable Risk (PAR) of 21.7% (Beydoun et al., 2014). In view of this high PAR, it is therefore likely that if plasma homocysteine could be lowered it would have a significant impact upon dementia incidence. In fact, lowering of homocysteine (by about 30%) is readily achieved by treatment with high doses of B vitamins. Two trials have shown that lowering homocysteine reduces age-related cognitive decline in normal ageing (Durga et al., 2007) and slows both brain atrophy and cognitive decline in people with MCI (VITACOG trial) (de Jager et al., 2012; Douaud et al., 2013; Smith et al., 2010). The effect of B vitamin treatment on people with MCI who have high baseline homocysteine is consistent with a disease-modifying effect (Smith & Refsum, 2017) but trials are needed to demonstrate that this treatment will slow conversion from MCI to dementia.
The Lancet Commission’s omission of high homocysteine as a modifiable risk factor is unfortunate since the treatment (B vitamins) is safe and inexpensive and could significantly benefit people with MCI and would be highly cost-effective (Tsiachristas & Smith, 2016). It was also unfortunate that the Commissions incorrectly reported a paper from the VITACOG trial (de Jager et al., 2012) as showing a lack of effect of B vitamins on global cognition whereas in fact the paper showed a significant slowing of decline in MMSE in those with high homocysteine who were treated with B vitamins.
References
View all comments by A. David SmithBeydoun, M. A., Beydoun, H. A., Gamaldo, A. A., Teel, A., Zonderman, A. B., & Wang, Y. (2014). Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health, 14(1), 643. doi:10.1186/1471-2458-14-643
de Jager, C. A., Oulhaj, A., Jacoby, R., Refsum, H., & Smith, A. D. (2012). Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. Int J Geriatr Psychiatry, 27(6), 592-600. doi:10.1002/gps.2758
Douaud, G., Refsum, H., de Jager, C. A., Jacoby, R., Nichols, T. E., Smith, S. M., & Smith, A. D. (2013). Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A, 110(23), 9523-9528. doi:10.1073/pnas.1301816110
Durga, J., van Boxtel, M. P., Schouten, E. G., Kok, F. J., Jolles, J., Katan, M. B., & Verhoef, P. (2007). Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet, 369(9557), 208-216.
McCaddon, A., & Miller, J. W. (2015). Assessing the association between homocysteine and cognition: reflections on Bradford Hill, meta-analyses and causality. Nutr Rev, 73(10), 723-735.
Smith, A. D., & Refsum, H. (2016). Homocysteine, B vitamins, and cognitive impairment. Annu Rev Nutr, 36, 211-239. doi:10.1146/annurev-nutr-071715-050947
Smith, A. D., & Refsum, H. (2017). Dementia prevention by disease-modification through nutrition. J Prev Alz Dis, in press. doi:http://dx.doi.org/10.14283/jpad.2017.16
Smith, A. D., Smith, S. M., de Jager, C. A., Whitbread, P., Johnston, C., Agacinski, G., . . . Refsum, H. (2010). Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment. A randomized controlled trial. PLoS ONE, 5(9), e12244. doi:10.1371/journal.pone.0012244.
Tsiachristas, A., & Smith, A. D. (2016). B-vitamins are potentially a cost-effective population health strategy to tackle dementia: Too good to be true? Alzheimers Dement (NY), 2, 156-161.
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