(folate, folic acid, holotranscobalamin, vitamin B12, vitamin B6, vitamin B9)
Risk Factor Type:
Nutrition and supplements
The reviewed studies do not provide consistent evidence for an association of B vitamin intake with risk of Alzheimer’s disease (AD). Some studies suggested an inverse association between folate levels and AD risk, but methodological limitations may have contributed to inconsistent findings across studies. Support for any association of vitamins B6 or B12 with AD was less apparent. Reviewed studies measured B vitamin status using either measures of dietary intake, usually recorded from food frequency questionnaires, or biomarker concentrations of the B vitamin itself or of a related marker as a measure of its bioavailability. Moreover, few studies addressed possible interactions between different B vitamins, or the possibility that B vitamins might have a role in preventing AD only among individuals with existing B-deficiencies. The majority of studies involved populations in the United States, where federal law mandates the fortification of flour with B vitamins and thus B vitamin deficiencies are uncommon. Additional prospective studies addressing these limitations will help clarify the issue. For a review of the putative mechanisms by which B vitamins may influence AD risk and detailed commentary on interpreting the findings below in a broader context, please view the Discussion.
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Last Search Completed:
03 November 2015
Koyama A, Weuve J, Jackson JW, O'Brien J, Blacker D. "B Vitamins." The AlzRisk Database. Alzheimer Research Forum. Available at: http://www.alzrisk.org. Accessed [date of access]*.
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The tables in the Risk Factor Overview present observational studies investigating the association between B vitamins and risk of Alzheimer’s disease (AD) and total dementia (TD). These studies investigated the role of different B vitamins (vitamin B6 [pyridoxine], vitamin B9 [folate], and vitamin B12 [cobalamin]) measured in a variety of contexts (dietary and supplement consumption, serum and plasma concentrations [including holotranscobalamin, the active form of B12]). There were no studies of other B vitamins (e.g., vitamin B3 [niacin], vitamin B1 [thiamine]) that met our eligibility criteria. Overall, findings varied to some extent by which B vitamin was studied, but did not generally provide consistent evidence of an association between B vitamins and risk of AD or TD. A large number of studies assessed the role of folate, with a mixture of both null findings and findings suggesting that higher levels of folate are associated with reduced AD and TD risk. In contrast, studies did not consistently show evidence of any association between levels of either vitamins B6 or B12 and risk of AD or TD. Some measures of B vitamins (holotranscobalamin, B-complex supplements) were only evaluated in one or two studies.
Potential Mechanism of Action
B vitamins may reduce AD risk through multiple mechanisms. The remethylation of homocysteine is catalyzed by methionine synthase, which requires vitamin B12 as a co-factor and a transfer of a methyl group from folate. This may result in several benefits to cognition through lower levels of circulating homocysteine, which may itself be neurotoxic and may increase oxidative stress. Homocysteine may also affect risk of dementia through increased cardiovascular risk (see Homocysteine). Vitamin B12 deficiency may also lead to inactivation of the enzyme methylmalonyl-CoA mutase, increasing levels of methylmalonyl-CoA, which may result in to neuronal damage and brain atrophy. Folate may also decrease levels of hippocampal amyloid-beta through increasing DNA methylation in the amyloid precursor protein promoter and in the presenilin 1 promoter, as well as through increasing DNA methyltransferase activity. Vitamin B6 is involved in the synthesis of several neurotransmitters such as dopamine, norepinephrine, serotonin, and gamma-aminobutyric acid and also serves as a cofactor in the transsulfuration pathway resulting in the metabolism of homocysteine into cystathionine and cysteine. Pyridoxal 5’-phosphate (PLP), the active form of vitamin B6, might reduce plasma concentrations of inflammatory markers through modulating immune function .
An ideal measure of B vitamins would represent long-term bioactive levels of the full range of these vitamins. Instead, the reviewed studies examined measures at only one time point, assessed only one (or a few) of these vitamins, and varied in how they assessed exposure.
Timing of exposure assessment. The reviewed studies used a single time point measurement of B vitamin exposure, which is unlikely to represent long-term exposure. Multiple measurements over time may better indicate long-term B vitamin exposure, and allow sensitivity analysis to assess any influence of incident comorbidities over the follow-up period. Moreover, a single time point measurement of B vitamin exposure is subject to greater measurement error, resulting in an underestimate of any association with incident AD[11, 12].
The majority of studies assessed B vitamin exposure primarily when participants were in their seventies. Because the pathology underlying AD dementia develops over an extended period, measurement of B vitamins in mid-life may be biologically more meaningful. Earlier life assessment of B vitamin intake using self-reported measures may also be less subject to measurement error from mild cognitive or functional impairment [15, 16]. Additionally, if some participants at baseline already have mild cognitive impairment, resulting in poorer nutrition and a lower intake of B vitamins, there might be reverse causation. Moreover, some studies had relatively short follow-up times of 2 to 4 years, a fairly brief period for participants to progress from normal cognition to dementia.
Intake versus biomarker measures. To measure B vitamin exposure, reviewed studies used either intake (dietary and/or supplemental) or biomarker concentrations (plasma or serum), with studies using the latter method reporting significant findings somewhat more frequently. Both methods present advantages and disadvantages in measuring B vitamin status to assess its relation with AD risk. Biomarker levels offer the advantage of not relying on participant recall, and a more accurate measure of bioavailability (particularly in older adults, who are more likely to have poor absorption).
Specifics of biomarker measures. Even within biomarker levels, however, there are differences among studies in exactly what is measured, and some studies may not have assessed the most appropriate measure of vitamin B status. For example, most studies measured vitamin B12 using serum or plasma concentrations, or through dietary intake. Very few studies measured plasma or serum holotranscobalamin (holoTC) or methylmalonic acid, both of which may be more sensitive and potentially biologically meaningful measures of vitamin B12 status.
Moreover, biomarker measures may not best represent average long-term levels due to high turnover in plasma. Although vitamin B12 in is reported to have a long half-life ranging from 480 to 1,284 days in plasma, other B vitamins have shorter half-lives ranging: 15 -20 days for vitamin B6, approximately 10 days for folate, and 1-2 hours for holoTC.
All but one reviewed study used plasma measures of B vitamins, the remaining one used serum measures. These are believed to be interchangeable, but there is poor correlation between serum and plasma concentrations for some biomarkers[22, 23] and the question hasn’t been formally addressed for B vitamins. However, the one study with serum measures did not have notably different results.
Measurement of dietary intake. To measure dietary and/or supplemental intake of B vitamins, the reviewed studies primarily used food frequency questionnaires (FFQ). One study used a 7-day food diary to measure total intake of B vitamins. All methods of dietary intake measurement were validated in prior studies. Although a food diary can record highly accurate information on dietary intake, the high burden of recording one’s diet may result in changes to a participant’s usual diet, resulting in non-differential or differential misclassification. Moreover, the high burden may also result in selection bias if participants who did not complete their food diaries were systematically different from those who did. For example, non-completing participants may have been older, have had a greater number of comorbidities, and/or have had a higher frequency of mild cognitive changes.
Design and Analysis
Confounding. As the reviewed studies included only observational studies, the possibility of bias from residual confounding remains. In particular, the majority of reviewed studies did not adjust for psychiatric comorbidities such as depression, which may affect both dietary habits and risk of AD. For example, depression may be associated with both lower diet quality and an increased risk of AD, potentially exaggerating a protective association between higher levels of B vitamins and AD risk. In addition, to the extent that depression is an early symptom of AD, this would be reverse causation – with the same resulting bias. On the other hand, if participants began supplement use and/or made beneficial dietary changes as a result of incident comorbidities that were not adequately adjusted for, B vitamins could spuriously appear harmful or their benefits underestimated.
It is also possible that the observed associations are confounded by other nutrients whose consumption is correlated with B vitamin intake. For example, healthy dietary patterns such as the Mediterranean diet are associated with increased B vitamin intake[24, 25]. Therefore, if other nutrients associated with healthy dietary patterns reduce AD risk, any associations between B vitamins and AD risk may be exaggerated. However, only results for folate showed evidence of reducing AD risk. As the majority of the studies involved participants in the United States, where folate fortification of flour is required, it is unlikely that the results were strongly confounded by other nutrients associated with a healthy dietary pattern.
Interactions. Studies did not generally assess possible interactions between different B vitamins, other dietary factors, lifestyle factors, and/or gene-diet interactions, although some evidence from related studies suggests that such an association may exist. For example, studies in the United States report that higher concentrations of plasma folate are associated with worse cognitive function among participants with the lowest concentrations of vitamin B12 [1, 26] . As these findings were generally not found in populations without mandatory fortification , or with voluntary fortification but lower mean folate intake , it is possible that excess folate was associated with cognitive impairment through the masking of pernicious anemia. Additionally, the association between vitamin B12 and cognitive function may also differ depending on APOE ε4 status, with low serum concentrations of B12 being most strongly associated with poor cognitive function among carriers of the ε4 allele.
How the exposure was modeled. Most reviewed studies modeled the association between AD risk and categories of B vitamin levels rather than treating B vitamin levels as continuous variables. Categorical measures of exposure have several advantages, including more power to detect non-linear associations and lower sensitivity to outlier exposures. However, categorical measures also present some disadvantages. For example, reviewed studies used different quantiles (e.g., above vs. below median, quintiles) as well as standard thresholds like Recommended Daily Intake, making comparisons difficult across studies. In addition, if B vitamin deficiencies are common among older adults[30, 31], there may be decreased power to detect any association using quantile-based comparisons if much higher levels are required for any cognitive benefit.
Results from Other Lines of Research
Prospective studies investigating the association between B vitamins and incident TD (not included in the tables because they did not report results for AD in particular) have similarly mixed results. Two studies did not find any significant association between plasma concentrations of folate and TD[32, 33], while others found that higher levels of red blood cell folate or total dietary intake of folate were associated with a lower risk of TD. Levels of vitamin B12 were not found to be associated with risk of TD in most studies measuring either plasma concentration or total dietary intake[32, 33, 35], except one study unexpectedly reporting a positive association between higher plasma concentrations of vitamin B12 and incident TD. A single study that evaluated the association between total dietary intake of vitamin B6 and risk of TD did not find any significant association.
Several studies have similarly evaluated the association between B vitamins and performance on cognitive tests or rates of decline in such performance. The majority of studies measured folate or vitamin B12 as plasma concentrations or dietary intake and found higher levels to be associated with better cognitive performance[37-41]. Fewer studies reported null findings[27, 42] and a single study reported unexpectedly that increased levels of total or dietary folate were significantly associated with cognitive decline. Only one study investigated vitamin B6, finding that both plasma concentrations and dietary intake were associated with a reduced risk of cognitive decline.
Although no randomized controlled trials (RCT) met inclusion criteria for our review, several have evaluated the effect of B vitamin supplements on cognitive test performance in older adults. One trial of folate supplements conducted among participants with high plasma concentrations of homocysteine, likely due to low folate, found better rates of cognitive change among those who received the active supplements, as opposed to placebo . A secondary prevention trial for cardiovascular disease found similar results using a treatment regimen of folate, vitamin B6 and vitamin B12, but only among a subgroup of participants with a low baseline intake of at least one B vitamin. In contrast, another trial among participants with a mild vitamin B12 deficiency did not report any significant associations between the assigned treatment (folate and vitamin B12) and cognitive decline, though this trial had a short follow-up time of 24 weeks. Other trials among participants without existing B vitamin deficiencies did not report any significant findings[46, 47].
Most research on B vitamins and other health outcomes pertains to the likely association of higher levels of folate, vitamin B6 and vitamin B12, with decreased cardiovascular disease risk through lowering homocysteine[48, 49]. Other studies have also investigated a possible benefit of B vitamins on improving muscle function, as well as bone mass, bone quality, and fracture risk. A small number of studies have suggested an association between higher levels of vitamin B6, folate, vitamin B12 and a decreased risk of depression in older adults[52, 53].
As B vitamins are water-soluble, excess amounts are eliminated through the urine, and toxic effects are few. The most common concern relates to high doses of folate leading to the masking of pernicious anemia (a form of B12 deficiency). In addition, long-term excessive use of vitamin B6 supplements may lead to motor and sensory neuropathy.
Discussion and Recommendations
Overall, the collective evidence from the reviewed studies is insufficiently consistent to warrant a recommendation to increase B vitamin intake for the prevention of AD. For folate, the reviewed studies do provide some support for an association between higher levels of folate and a reduced risk of AD, but findings vary across studies. For vitamins B6 and B12, there is more consistent evidence that they are not associated with risk of AD. However, data from clinical trials suggest B vitamins may have a protective effect on AD risk specifically among individuals who are B-deficient. Overall, good clinical practice already supports maintaining adequate B vitamin intake (particularly folate and B12) for general and cognitive health. Toxic effects from dietary B vitamin intake are rare, and B vitamins may protect against other diseases, such as cardiovascular disease, by decreasing levels of homocysteine and reducing its pro-inflammatory effects. To address the limitations of existing studies, future studies should be designed to address the differential effects of B vitamins among individuals with and without existing deficiencies, using the most appropriate measures of long-term B vitamin status that reflect its potential impact on the brain.
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24. Castro-Quezada, I., B. Roman-Vinas, and L. Serra-Majem, The Mediterranean diet and nutritional adequacy: a review. Nutrients, 2014. 6(1): p. 231-48.
25. Kim, J., et al., Dietary Patterns Derived by Cluster Analysis are Associated with Cognitive Function among Korean Older Adults. Nutrients, 2015. 7(6): p. 4154-69.
26. Morris, M.S., et al., Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr, 2007. 85(1): p. 193-200.
27. Doets, E.L., et al., Interactions between plasma concentrations of folate and markers of vitamin B(12) status with cognitive performance in elderly people not exposed to folic acid fortification: the Hordaland Health Study. Br J Nutr, 2014. 111(6): p. 1085-95.
28. Clarke, R., et al., Folate and vitamin B12 status in relation to cognitive impairment and anaemia in the setting of voluntary fortification in the UK. Br J Nutr, 2008. 100(5): p. 1054-9.
29. Feng, L., et al., Vitamin B-12, apolipoprotein E genotype, and cognitive performance in community-living older adults: evidence of a gene-micronutrient interaction. Am J Clin Nutr, 2009. 89(4): p. 1263-8.
30. Clarke, R., et al., Vitamin B12 and folate deficiency in later life. Age Ageing, 2004. 33(1): p. 34-41.
31. Selhub, J., et al., B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr, 2000. 71(2): p. 614S-620S.
32. Hendrie, H.C., et al., Homocysteine levels and dementia risk in Yoruba and African Americans. Int Psychogeriatr, 2013. 25(11): p. 1859-66.
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34. Ramos, M.I., et al., Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr, 2005. 82(6): p. 1346-52.
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37. Clarke, R., et al., Low vitamin B-12 status and risk of cognitive decline in older adults. Am J Clin Nutr, 2007. 86(5): p. 1384-91.
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41. Tucker, K.L., et al., High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study. Am J Clin Nutr, 2005. 82(3): p. 627-35.
42. Mooijaart, S.P., et al., Homocysteine, vitamin B-12, and folic acid and the risk of cognitive decline in old age: the Leiden 85-Plus study. Am J Clin Nutr, 2005. 82(4): p. 866-71.
43. Morris, M.C., et al., Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. Arch Neurol, 2005. 62(4): p. 641-5.
44. Durga, J., et al., Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet, 2007. 369(9557): p. 208-16.
45. Eussen, S.J., et al., Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial. Am J Clin Nutr, 2006. 84(2): p. 361-70.
46. Ford, A.H., et al., Vitamins B(12), B(6), and folic acid for cognition in older men. Neurology, 2010. 75(17): p. 1540-7.
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50. Mithal, A., et al., Impact of nutrition on muscle mass, strength, and performance in older adults. Osteoporos Int, 2013. 24(5): p. 1555-66.
51. Dai, Z. and W.P. Koh, B-vitamins and bone health--a review of the current evidence. Nutrients, 2015. 7(5): p. 3322-46.
52. Almeida, O.P., et al., B-vitamins reduce the long-term risk of depression after stroke: The VITATOPS-DEP trial. Ann Neurol, 2010. 68(4): p. 503-10.
53. Nanri, A., Nutritional epidemiology of type 2 diabetes and depressive symptoms. J Epidemiol, 2013. 23(4): p. 243-50.