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3 Tufts-New England Medical Center Evidence-based Practice Center, Institute for Clinical Research and Health Policy Studies, Tufts-New England Medical Center, Boston, MA 02111 and 4 Nutrition and Neurocognition Laboratory (IHR) and Cardiovascular Nutrition Laboratory (AHL), Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111
* To whom correspondence should be addressed. E-mail: alice.lichtenstein{at}tufts.edu
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ABSTRACT |
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 TOP ABSTRACT IntroductionMethodsResultsDiscussionLITERATURE CITED |
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Introduction |
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TOPABSTRACTIntroductionMethodsResultsDiscussionLITERATURE CITED |
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Proposed mechanisms for the neurotoxic consequences of compromised B-vitamin status and hyperhomocysteinemia include hypomethylation of nucleic acids and neurotransmitters, increased oxidative stress, and increased ß amyloid synthesis (6). Elevated homocysteine levels may also directly overstimulate N-methyl-D-aspartate receptors resulting in neurotoxicity due to calcium influx and apoptosis. Folate and vitamin B-12 are essential for methionine synthesis and to the formation of a universal methyl donor, S-adenosylmethionine, important to the generation of neurotransmitters, phospholipids, and myelin (2,7).
Given the complexity of the mechanisms related to cognitive changes in the elderly, and the metabolic relationship between B vitamins and homocysteine levels, the association between B-vitamin status and subsequent cognitive function remains unclear. This systematic review of observational studies investigates the association between blood levels or dietary intake of B vitamins and the risk and progression of neurocognitive deficit as measured by cognitive tests and age-related neurodegenerative disorders such as Alzheimer's disease in humans. The terms "B vitamin" or "vitamin B" in this article refers to the vitamins of interest (folate, vitamin B-6, and vitamin B-12).
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Methods |
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TOPABSTRACTIntroductionMethodsResultsDiscussionLITERATURE CITED |
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We included longitudinal cohort and case-control studies of human adult participants that evaluated blood concentrations or dietary intake of B vitamins with the risk or odds of outcomes related to diagnosis or degree of severity of Alzheimer's disease and performance on cognitive function tests. We excluded studies that focused on mental retardation, Wernicke's encephalopathy, subacute combined degeneration, acute encephalopathy, peripheral neuropathy and other lower motor neurodegeneration, and evaluations of outcomes related to depression and other psychiatric conditions. Studies of vascular and mixed causes of dementia lacking separate analyses for Alzheimer's disease were excluded. We excluded studies that limited their analyses to homocysteine and did not evaluate the role of B vitamins on tests of cognitive function and Alzheimer's disease. Studies of cross-sectional designs or studies that provided only cross-sectional correlation data (8) and B-vitamin intervention trials (9) were excluded from our review and are discussed elsewhere.
A single reviewer performed data extractions of each accepted article and a second reviewer independently verified the data. Discrepancies were resolved through consensus. We evaluated all study outcomes relevant to Alzheimer's disease, cognitive impairment, or cognitive-function tests.
Study quality. A 3-category grading system was used to denote the quality of each study included in our review (8,10). Each study was graded by at least 2 people, and disagreements were resolved through consensus.
Good: Results were valid without obvious major bias. The study provided a clear description of the population including a description of cases and comparison groups, settings, B-vitamin measurement technique and status, and used appropriate outcome measurement (e.g., diagnosis of Alzheimer's disease using validated clinical criteria and/or histopathological methods), appropriate statistical and analytic methods (including adjustment for other risk factors such as homocysteine and ApoE), had no reporting errors, had <20% dropout, and clearly reported reasons for dropouts.
Fair: The study had some deficiencies or was susceptible to some bias but not major bias. The study might be missing information, making assessment of the limitations and potential problems difficult, but omissions were not sufficient to invalidate the results. This category included studies that did not meet all the criteria in the "good" category.
Poor: Significant bias was present that could invalidate results. Study had serious errors in design, analysis, or reporting, or had large amounts of missing information or discrepancies in reporting.
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Results |
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TOPABSTRACTIntroductionMethodsResultsDiscussionLITERATURE CITED |
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Low baseline blood folate concentration was consistently associated with poorer global cognitive domain test performance at follow-up. Studies used several types of instruments to assess the same cognitive domain and the definition of low folate status was not consistent across studies.
Blood concentrations of vitamin B-6 and cognitive-test performance. Two prospective cohort studies evaluated the association between vitamin B-6 blood concentrations and cognitive-test performance in cognitively intact aging subjects over a 3–7 y period (Table 2) (12,14). The studies had 499 and 321 subjects, were graded fair quality, but each evaluated the association of different pyridoxal-5'-phosphate (PLP) thresholds (35.2 and 86.1 nmol/L) and a wide range of cognitive domains.
Neither study reported a significant association between blood concentrations of vitamin B-6 and 6 different cognitive subtests with the exception of 1 subtest assessing a spatial copying score (P < 0.01); in this case, low baseline vitamin B-6 concentrations were associated with poorer test scores at follow-up (14). However, this association was no longer significant after adjusting for other B-vitamin levels and homocysteine. Overall, the limited data did not support an association between blood vitamin B-6 levels and cognitive deficit.
Blood concentrations of vitamin B-12 blood and cognitive-test performance. Eight studies (7 prospective cohort and 1 case-control) evaluated the association of vitamin B-12 blood concentrations and cognitive-test performance in cognitively intact or impaired aging subjects; the follow-up period ranged from 3 to 8 y (Table 2) (11,12,14–18,20). Sample sizes ranged from 80 to 700 subjects. Six studies were graded fair quality and 2 were of poor quality. The 8 studies evaluated thresholds of low vitamin B-12 concentrations that ranged from 221.4 to 516.6 pmol/L, and analyses were adjusted for a variety of confounders. Four studies compared high and low mean blood concentrations of vitamin B-12 (11,12,14,17), 3 studies used quantile comparisons (15,16,20), and 1 study (18) reported only qualitative data.
Two of the 8 studies reported a significant positive association in memory and visual motor integration subtests at follow-up in subjects with baseline vitamin B-12 blood levels (11,14). One of these studies reported that significance did not persist after adjusting for other B vitamins and plasma homocysteine levels (14); the other study [Elias et al. (11)] did not report analyses adjusted for plasma homocysteine levels. The rate of change in cognitive-test performance was analyzed in 4 studies. Lower baseline blood concentrations of vitamin B-12 did not predict rate of cognitive decline (14–17).
There was no discernible pattern of association between vitamin B-12 blood concentrations and changes in performance in any particular cognitive domain. A significant association was attenuated after adjusting for confounders. Vitamin B-12 blood concentrations were not associated with cognitive decline over time.
Blood concentrations of vitamin B and Alzheimer's disease.
Ten studies (5 prospective cohort and 5 case-control studies) evaluated the risk of incident or prevalent Alzheimer's disease with blood concentrations of vitamin B (Table 3) (13,20,22–26,28,29,34). One study was rated good, 7 fair, and 2 poor. One study evaluated all 3 B vitamins (24); 7 studies evaluated both folate and vitamin B-12 (20,22,23,25,26,29,32); 1 case-control study evaluated only vitamin B-6 levels (34); and 1 prospective cohort evaluated only folate levels (13). The 5 prospective cohort studies included sample sizes ranging from 350 to 
1100 cognitively intact or impaired subjects followed over a 2–8 y period. The 5 case-control studies included 618 subjects with Alzheimer's disease and 535 controls. Three studies compared high and low mean blood levels of vitamin B (22,23,34), 5 studies used quantile comparisons (13,20,26,28,29), and 2 studies reported qualitative data (24,29). Alzheimer's disease was determined by validated clinical criteria in all studies; in addition, 2 studies utilized brain imaging and/or histopathology when available (24,26).
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Vitamin B intake and cognitive function. Two prospective cohort studies, of good and fair quality evaluated associations between dietary intake of all 3 B-vitamins and cognitive-test performance (14,30). A third poor quality prospective cohort study evaluated only vitamin B-6 intake in association with cognitive-test performance (31). Sample sizes ranged from 90 to 3700, mostly of cognitively intact subjects with follow-ups of 6 mo to 3 y. Dietary intakes of food and supplements were assessed through FFQ. The fair study, by Tucker et al. (14), reported that among 6 different cognitive function subtests, significant associations with B-vitamin intake were not found, with the exception of the construction praxis spatial copying score (P < 0.05), where better cognitive-test performance was associated with increased B-vitamin intake. The good quality study, by Morris et al. (30), reported a slower decline in cognitive-test performance over a 6-y period in subjects with high vitamin B-12 intake but faster decline among subjects with a high folate intake (>400 µg/d) from either food sources or supplements. The poor quality study, by Deijen et al. (31), reported no association between vitamin B-6 intake and changes in cognitive function.
Dietary intakes of B vitamins and incidence or prevalence of Alzheimer's disease were evaluated in 2 studies: 1 prospective cohort, graded as fair, and 1 case-control, graded as poor (32,33). Mizrahi et al. (32) reported lower dietary intakes of folate and vitamin B-6 among subjects with Alzheimer's disease than among normal controls, whereas Morris et al. (33) reported no significant association between intakes of all 3 B vitamins and the incidence of Alzheimer's disease over a 4-y period.
Overall, these limited data do not support an association between folate, vitamins B-6, and vitamin B-12 intake and cognitive-test performance or Alzheimer's disease.
Plasma homocysteine concentrations and cognitive function. Six of 10 studies that evaluated blood concentrations of vitamin B and cognitive-test performance also reported an association between plasma homocysteine concentrations and cognitive function (11,12,14,15,17,20). Five of the studies were graded as fair and 1 study was graded as poor. Two studies reported no association (12,17) and 4 (3 cohort and 1 case-control) reported a significant association between poor cognitive-test performance at follow-up in subjects with higher baseline plasma homocysteine concentrations after adjusting the analyses for baseline blood concentrations of vitamin B (11,14,15,20).
Among the 10 studies that assessed the association between B vitamins and Alzheimer's disease, 6 studies assessed the association between homocysteine levels and Alzheimer's disease (20,23–26,28). Two studies reported no association (25,28), and 4 studies (20,23,24,26) (2 cohort and 2 case-control) reported an association between higher baseline homocysteine levels and an increased risk for Alzheimer's disease that persisted after adjusting for B-vitamin blood concentrations.
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Discussion |
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TOPABSTRACTIntroductionMethodsResultsDiscussionLITERATURE CITED |
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Despite these limitations, the majority of studies evaluating blood folate concentrations reported a positive association between low baseline folate levels and poor test performance at follow-up. This association was consistent for global cognitive function. Studies also reported an association between low blood folate concentrations and an increased risk of Alzheimer's disease. However, among studies, the definition of low blood folate status was variable, making comparisons across studies tenuous. Generally, most studies noted an increased risk for poor cognitive function only for extreme contrasts of blood folate concentrations (i.e., comparing the subgroups of subjects in the lowest and highest quantiles).
The evidence from longitudinal cohort and case-control studies suggests that there is no significant association between blood concentrations or the dietary intake of vitamin B-6 and B-12 and cognitive-test performance or Alzheimer's disease. Although 25% of the studies reported higher vitamin B-12 blood concentrations to be associated with better cognitive-test performance, no consistent pattern of association with a particular cognitive domain was reported, or else the positive association was attenuated after adjusting the analyses for confounders.
The studies of dietary folate intake and cognitive-test performance were equivocal. One study, graded as good (30), reported an increased rate of cognitive decline with increased folate intake, whereas another study, graded as fair, reached the opposite conclusion (14). The clinical significance of this effect remains unclear because the former study found a poorer outcome in global composite score measured as the mean of 4 subtests scores, whereas the latter found an improved test performance in 1 of 5 cognitive subtests.
Approximately 66% of the B-vitamin association studies reported data on homocysteine or adjusted the B-vitamin analyses for homocysteine levels. The 3 B vitamins (folate, vitamin B-6, and vitamin B-12) are involved in the metabolism of homocysteine and thus any associations between B-vitamin status and cognitive function would not be expected to be biologically independent of homocysteine. Notably, studies that reported a significant association between low blood folate and poor cognitive performance also reported an association between increased plasma homocysteine concentrations and decreased performance on cognitive tests or an increased prevalence of Alzheimer's disease. However, our review did not evaluate the potential association of homocysteine alone on cognitive deficit.
Future research endeavors are necessary to evaluate a threshold level for low concentrations of vitamin B that are associated with poorer test performance in the different cognitive domains. Because blood concentrations of the B vitamins may not be a good indicator of their concentrations in tissues or cells, additional outcome measures should include biomarkers of B-vitamin status, such as methylmalonic acid (MMA) and holotranscobalamin. When possible, ongoing and future research should implement suggestions generated from our review with regard to the measurement of B vitamins and the assessment of cognitive function.
In our previous systematic review of B-vitamin supplement trials, we reported that the evidence remains inconclusive, although folic acid supplementation may benefit specific populations and age groups (9). However, firm conclusions were not possible because of the small number of trials and participants. Thus, the analyses of both trial and cohort studies failed to support any associations between blood concentrations, dietary intake, or supplementation with vitamin B-6 or vitamin B-12 and neurocognitive outcomes, and showed inconsistent associations with folate.
In conclusion, data supporting an association between low blood concentrations of the B vitamins and increased risk for, or progression of, poor neurocognitive outcomes is limited due to the absence of good-quality studies, heterogeneity in assessment methodology, and a lack of standardized threshold levels for categorizing low B-vitamin status. There are, at best, minimal data to support an association between vitamins B-6 and B-12 and cognitive function. Despite the fact that low baseline blood folate concentrations did predict poorer cognitive function at follow-up in the majority of studies, the heterogeneity of the evidence diminished the validity of an overall association.
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FOOTNOTES |
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2 Author disclosures: G. Raman, A. Tatsioni, M. Chung, I. H. Rosenberg, J. Lau, A. H. Lichtenstein, and E. M. Balk, no conflicts of interest.
Manuscript received 15 March 2007. Initial review completed 4 April 2007. Revision accepted 14 May 2007.
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