Vitamin B12,B6,or Folate and Cognitive Function in Community-Dwelling Older Adults: A Systematic Review and Meta-Analysis

Abstract

Background:

Previous studies have indicated that B vitamin deficiencies are an essential cause of neurological pathology. There is a need to provide evidence of the benefit of B vitamins for the prevention of cognitive decline in community-dwelling older adults.

Objective:

To examine the association between intake and plasma levels of vitamins B12, B6, and folate and cognitive function in older populations through a systematic review and meta-analysis.

Methods:

Medline (PubMed), EMBASE, and Cochrane databases were used to search the literature though August 8, 2019. We included observational population-based studies evaluating the association between concentrations or intake levels of vitamins B6, B12, or folate and cognition in older adults aged ≥45 years. The quality of all studies was assessed by the modified Newcastle-Ottawa Scale. Odds ratios (ORs) and hazard ratios (HRs) were analyzed by the random-effects model. Sensitivity analyses were conducted by excluding the studies with significant heterogeneity.

Results:

Twenty-one observational studies with sample sizes ranging from 155–7030 were included in the meta-analysis. Higher levels of vitamin B12 (OR = 0.77, 95% CI = 0.61–0.97) and folate concentration (OR = 0.68, 95% CI = 0.51–0.90) were associated with better cognition in cross-sectional studies, but not in sensitivity analyses or prospective studies. High vitamin B6 concentrations showed no significant benefit on cognition and dementia risk. Prospective studies did not provide substantial evidence for the relationship.

Conclusion:

The results from our meta-analysis suggest that vitamins B12, B6, and folate may not be modifiable risk factors for slowing cognitive decline among community-dwelling older individuals.

Keywords

Alzheimer’s disease cognitive decline dementia folate nutrition vitamin B6 vitamin B12

INTRODUCTION

Cognitive decline, as observed in mild cognitive impairment (MCI), Alzheimer’s disease (AD), and other dementias, has been one of the most common and costly chronic conditions contributing to decreases in the quality of life [1 –6]. According to the National Center of Health Statistics (NCHS) and World Alzheimer Report 2015, the number of dementia patients worldwide will triple to 135.5 million by 2050 [7]. Dementia has become the sixth leading cause of death in all populations [7]. However, due to the unclear pathogeny, no effective strategies are available for preventing or treating this neurological disorder in late life.

Clinical practice guidelines have indicated that some malnourished conditions, such as deficiency of vitamin B12 or folate, are causes of dementia [8], and vitamin B12 supplements may reduce the risk of cognitive decline [9]. However, the current studies on vitamin status in the community population have not concluded consistently. Most observational studies conflated vitamin deficiencies with sub-optimal vitamin status, but they focused on sub-optimal vitamin status actually. Given the high prevalence of dementia and cognitive impairment in older adults and its significant consequences, it is critical to explore the role of B vitamin as a modifiable risk factor associated with indirect pathogenetic disease processes. Over the past few years, studies exploring the relationship between B vitamins, e.g., vitamin B12, folate, and vitamin B6, and cognitive impairment in community-dwelling older adults have been published. A few meta-analysis have also summarized the relationship between B vitamins and the risk of dementia, but with inconsistent conclusions [10 –12]. The reasons may be because of the considerable heterogeneity in the studies they recruited, especially where the general concept of B vitamins included combinations of vitamin B12, folate, and vitamin B6 as the exposure measurement.

This study aims to assess the relationship between individual B vitamins, including vitamin B12, folate, and vitamin B6, and cognitive decline in older adults, through a systematic review and meta-analysis of published population-based studies with cross-sectional and prospective designs.

METHODS

This meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA-2009) [13] and Meta-Analysis for Observational Studies in Epidemiology (MOOSE) guidelines [14].

Search strategy

Studies were selected based on the following inclusion criteria: 1) community-based samples (N≥100); 2) aged human participants (>45 years); 3) observational (prospective or cross-sectional) design; 4) incorporated outcomes on incidence and prevalence of dementia or cognitive decline (e.g., decrease in Mini-Mental State Examination (MMSE) scores); 5) individual B vitamin exposure (vitamin B12, folate, or vitamin B6), blood concentrations, or intake levels; 6) reported effect estimates appropriate for the pooled analysis of effect sizes, such as odds ratios (ORs), hazard ratios (HRs), or other types of estimates, such as correlation or regression coefficients, that could be converted to the above indexes; and 7) results adjusted for covariates (at least by age, and sex).

We searched the PubMed, Cochrane library, and EMBASE databases from the inception date to August 8, 2019, with the search terms in Supplementary Table 1.

Table 1

Modified Newcastle-Ottawa Scale (NOS) for quality assessment of observational studies

Reference	Participants	Sample size/power calculation	Confounders	Statistical analyses	Missing data	Appropriate outcome measurement	Objective measure of outcome
Palacios et al. 2019 [19]	3	unclear	3	3	unclear	3	3
Hughes et al. 2017 [28]	2	unclear	2	3	3	3	3
Mendonca et al. 2017 [17]	3	unclear	3	3	3	3	3
Castillo-Lancellotti et al. 2015 [26]	2	unclear	2	2	unclear	3	3
Hooshmand et al. 2012 [32]	3	unclear	3	3	unclear	3	3
Lildballe et al. 2011 [29]	2	unclear	2	3	unclear	3	3
Brown et al. 2011 [33]	3	unclear	3	3	unclear	3	3
Fischer et al. 2008 [24]	3	unclear	3	3	3	3	3
Clarke et al. 2008 [30]	3	unclear	3	3	unclear	3	3
Hin et al. 2006 [34]	3	unclear	1	2	3	3	3
Ramos et al. 2005 [27]	2	unclear	2	3	unclear	3	3
Kado et al. 2005 [25]	3	unclear	3	3	unclear	3	3
Maxwell et al. 2002 [18]	2	unclear	1	2	unclear	3	3
Wang et al. 2001 [31]	2	unclear	1	3	2	3	3
Kim et al. 2019 [35]	3	unclear	3	3	unclear	3	3
Lefevre-Arbogast et al. 2016 [36]	3	unclear	2	3	3	3	3
Agnew-Blais et al. 2015 [23]	2	unclear	3	3	unclear	3	3
Nelson et al. 2009 [20]	3	unclear	2	3	unclear	3	3
Vercambre et al. 2009 [21]	2	unclear	3	2	unclear	3	3
Luchsinger et al. 2007 [22]	2	unclear	2	2	unclear	3	3
Morris et al. 2006 [37]	3	unclear	2	2	unclear	3	3

*0 = definitely no (high risk of bias); 1 = mostly no; 2 = mostly yes; 3 = definitely yes (low risk of bias).

Table 2

Characteristics of the included studies for vitamin B12, folate, and vitamin B6

Included studies	Design	Age (y)	Sample size (n)	Follow-up time (y)	Vitamin B exposure	Baseline MMSE (SMMSE)	Baseline B vitamin range	Number of cases in longitudinal analysis	Outcome
Mendonca et al. 2017 (UK) [17]	Prospective and Cross-sectional study	85+	Baseline: 752–765; Follow-up: 311–318	3	Plasma vitamin B12 (pmol/L, quartile); RBC folate (nmol/L, quartile)	SMMSE range: 22–29	Folate: 451–1287 (quartile); Vitamin B12 : 170–324 (quartile)	138	SMMSE
Hughes et al. 2017 (UK) [28]	Prospective study	60+	155	4	Serum total B12 (pmol/L, tertile); RBC folate (nmol/L, tertile); PLP, pyridoxal-5-phosphate (nmol/L, tertile)	MMSE, mean±SD: 29.1±1.3	Biomarker status: RBC folate: 954±410; serum B12 : 282±106; vitamin B6 : 58.4±25.8	19	MMSE
Hooshmand et al. 2012 (Finland) [32]	Prospective study	65–79	274	7	Serum folate (nmol/L, quartile)	MMSE range: 18–30	Serum folate: 1.8–29.2	Continuous variable	MMSE
Brown et al. 2011 (USA) [33]	Prospective and Cross-sectional study	70–79	499	7	Serum vitamin B12 (pmol/L, quartile); serum folate (nmol/L, quartile); serum vitamin B6 (pmol/mL, quartile)	Cognitive score: 0–89. Cognitive decline was analyzed as binary variables after dichotomization at the 25th percentile	Vitamin B12, mean±SD: 460.96±385.09 (APOEɛ4); folate, mean±SD: 8.33±14.51 (APOEɛ4); vitamin B6, mean±SD: 68.12±58.58 (APOEɛ4)	Not reported	Cognitive decline
Fischer et al. 2008 (Austria) [24]	Prospective study	75+	488	2.5	Blood folic acid (nmol/L, continuous variable)	–	9.8±5.1 (healthy); 8.7±4.1 (Possible AD); 6.9±2.8 (Probable AD)	90	Dementia
Kado et al. 2005 (USA) [25]	Prospective and Cross-sectional study	70–79	499	7	Plasma vitamin B12 (pmol/mL, quartile); Plasma folate (nmol/mL, quartile); Plasma vitamin B6 (pmol/mL, quartile)	Cognitive score: 0–89. Cognitive decline was analyzed as binary variables after dichotomization at the 25th percentile	Vitamin B12 : 440.6±358.3; folate: 6.62±5.59; vitamin B6 : 70.1±64.5	Not reported	Cognitive decline
Maxwell et al. 2002 (Canada) [18]	Prospective study	65+	266	5	Folate (nmol/L, quartile)	3MSE: 74.8±15.8	5–36	87	3MSE
Wang et al. 2001 (Sweden) [31]	Prospective study	75+	370	3	Vitamin B12 (pmol/L); folate (nmol/L)	–	B12 ≤150 vs >150; folate ≤10 vs >10	59	Dementia
Palacios et al. 2019 (USA) [19]	Prospective and Cross-sectional study	45–75	949	2	Plasma vitamin B6 (pmol/mL, tertile)	MMSE: 23.9±3.0	7.2–737	157	MMSE
Lefevre-Arbogast et al. 2016 (France) [36]	Prospective study	67.7–94.9	1321	7.4	Vitamin B12 intake (μg/day, quintile) and folate intake (μg/day, quintile) and vitamin B6 intake (mg/day, quintile)	–	Vitamin B12 : 5.7±11.4; folate: 278.3±134.8; vitamin B6 : 1.5±0.6	197	Dementia
Agnew-Blais et al. 2015 (USA) [23]	Prospective study	65–79	7030	5	Vitamin B12 intake (μg/day, quartile); folate intake (μg/day, quartile); vitamin B6 intake (mg/day, quartile)	–	Vitamin B12 : 2.4–12.7 (quartile); folate: 241.25–695.67 (quartile); vitamin B6 : 1.5–3.79 (quartile)	307	MCI/probable dementia
Nelson et al. 2009 (USA) [20]	Prospective study	65+	3634	10	Vitamin B12 intake (μg/day, quintile); folate intake (μg/day, quintile); vitamin B6 intake (mg/day, quintile)	–	Vitamin B12 : 3.4–20.1 (quintile); folate: 209–429 (quintile); vitamin B6 : 1.6–2.6 (quintile)	212	AD
Vercambre et al. 2009 (France) [21]	Prospective study	76–82	4809	13	Vitamin B12 intake (μg/day, continue); folate intake (μg/day, continue); vitamin B6 intake (mg/day, continue)	–	Vitamin B12 : 7.71±4.81; folate: 401.4±117.0; vitamin B6 : 1.76±0.48	598	Cognitive decline
Luchsinger et al. 2007 (USA) [22]	Prospective study	65+	965	6.1	Vitamin B12 intake (μg/day, quartile); folate intake (μg/day, quartile); vitamin B6 intake (mg/day, quartile)	–	Vitamin B12 : 3.5–13.5 (quartile); folate: 292.9–487.9 (quartile); vitamin B6 : 2.3–4.5 (quartile)	192	Dementia
Morris et al. 2006 (USA) [37]	Prospective study	65+	1041	3.9	Vitamin B12 intake (μg/day, quintile); folate intake (μg/day, quintile); vitamin B6 intake (mg/day, quintile)	–	Vitamin B12 : 0.5–127.8 (quintile); folate: 90–1660 (quintile); vitamin B6 : 0.6–100.9 (quintile)	162	Dementia
Castillo-Lancellotti et al. 2015 (Chile) [26]	Cross-sectional study	65+	1051		Vitamin B12 (pg/ml, continue)	–	Normal: 341.19±7.9; cognitive impairment: 386.11±20.52	–	–
Lildballe et al. 2011 (UK) [29]	Cross-sectional study	75+	839		Serum vitamin B12 (pmol/mL, tertile)	–	Normal: 85–600; cognitive impairment: 140–480	–	–
Clarke et al. 2008 (UK) [30]	Cross-sectional study	65+	2403		Serum vitamin B12 (pmol/L,tertile) and folate (nmol/L, tertile)	–	Vitamin B12 : 167–371 (tertile); folate: 7.3–42.1 (tertile)	–	–
Hin et al. 2006 (UK) [34]	Cross-sectional study	75+	1000		Serum vitamin B12 (pmol/L, quartile) and folate (nmol/L, quartile)	–	Vitamin B12 : 125–350 (quartile); folate: 11–55.3 (quartile)	–	–
Ramos et al. 2005 (USA) [27]	Cross-sectional study	60+	1789		RBC folate (ng/mL, continue)	–	Range: 50–900	–	–
Kim et al. 2019 (Korea) [35]	Cross-sectional study	60+	200		Serum vitamin B12 (pg/mL, quartile); Serum folate (ng/mL, quartile)	–	Vitamin B12: normal: 741.5±1088.0; cognitive impairment: 520.7±284.6; folate: normal: 9.64.1; cognitive impairment: 8.9±5.3	–	–

MMSE, Mini-Mental State Examination; SMMSE, Standardized Mini-Mental State Examination; 3MSE, Modified Mini-Mental State Examination.

Data extraction

Data extraction involved retrieval of the study design, population characteristics (including sample size and age), years of follow-up, exposure to B vitamins, and outcome indicators (Table 2).

To reduce the heterogeneity of outcome indicators among different studies, we focused on two indicators of cognitive decline assessment: MMSE as the assessment of global cognitive function and a diagnosis of dementia by particular criteria. If an article from the same cohort reported both cross-sectional and longitudinal results, we included each of these results separately.

Statistical analysis

The quality of articles was assessed by using the modified Newcastle-Ottawa scale for observational studies (Table 1). Four domains (selection bias, performance bias, detection bias, and information bias) were rated by this scale.

Categorized exposure or continuous exposure was analyzed as subgroup analysis. The effect measurement of lowest versus highest B vitamin categories was adopted. The definitions of ‘lowest’ and ‘highest’ B vitamin categories were based either on threshold values defined a priori or on population-based percentile so that these may vary across studies.

The combined effect size was estimated by a random effects model [15]. Heterogeneity was assessed using the I² statistic with percentage cut-offs of 25%, 50%, and 75% corresponding to low, moderate, and high heterogeneity, respectively. Sensitivity analyses were conducted by excluding the studies that introduced significant heterogeneity. Egger’s regression test was used to assess publication bias. If a sufficient number of publications were available (n = 10), publication bias was assessed via funnel plots (visually) [16].

Statistical significance is p < 0.05 (two-tailed). Statistical analyses were performed using STATA 15.1.

RESULTS

Literature search and study characteristics

We identified a total of 642 articles, including 359 articles from PubMed, 281 from EMBASE, and 2 from COCHRANE. Two hundred six articles were excluded because they were duplicates. After reviewing 436 articles’ titles and abstracts, we selected 55 articles for further evaluation. After applying the inclusion and exclusion criteria and excluding studies with insufficient data for the meta-analysis, our analysis included 21 studies. The studies are outlined in Table 2, including 6 cross-sectional, and 15 longitudinal studies. Four prospective studies of the 15 longitudinal studies also reported cross-sectional results. Sample sizes ranged from 155 to 7030. The follow-up duration ranged from 2 years to 13 years. Six prospective studies included cognitively impaired participants at baseline [17 –22].

Most studies included two genders, and one study included only women [23]. Five studies reported exposure to B vitamins as a continuous variable [21 , 24–27], and 16 studies reported it as a categorical variable. Three studies used tertiles [19 , 28–30], 2 studies used binary indicators [31], 8 studies used quartiles [17 , 32–35], and 3 used quintiles [20 , 37].

Sixteen studies reported cognitive function as continuous scores [17–21 , 32–34], and 6 studies classified cognitive function dichotomously [22 , 35–37]. Among the 23 studies that used neuropsychological tests, 14 studies measured global cognition using the Mini-Mental State Examination (MMSE, SMMSE, or 3MSE (n = 11)), and 6 studies used a diagnosis of dementia or AD based on the DSM criteria.

Methodological quality

Overall, studies were deemed good quality (low to moderate levels of bias). The most common source of bias was a lack of a power analysis. Most studies did not report how they handled missing data; however, participant characteristics of the lost participants were well documented. All studies performed multivariate adjustments. Commonly adjusted covariates included age, gender, education, season of blood collection, physical inactivity, smoking, alcohol, APOE, and depression.

Fig.1

Literature Search and Screening Process.

Association between vitamin B12 and cognition

Individuals with high vitamin B12 blood concentrations had a lower risk of dementia compared to those with low vitamin B12 concentrations (OR = 0.77, 95% CI = 0.61–0.97) in cross-sectional studies (Fig. 2A). The heterogeneity among the studies was high (I² = 76.9%) and disease bias was present (p < 0.05). The results of the stratified analysis showed that studies with vitamin B12 blood concentrations grouped in quartiles or quintiles had lower heterogeneity (I² = 21.3%) and no publication bias; in these studies, there was no correlation between vitamin B12 and the risk of dementia (OR = 0.77, 95% CI = 0.57–1.04). Studies that were grouped by binary or tertile categories had higher heterogeneity and publication bias but also showed that the correlation between vitamin B12 and the risk of dementia was not statistically significant. Sensitivity analysis did not present a significant association after excluding four studies [26 , 34] that contributed to the high level of heterogeneity (OR = 0.92; 95% CI = 0.68–1.23). No significant association was found in prospective studies that assessed either vitamin B12 blood concentrations (OR = 1.27; 95% CI = 0.97–1.67) or vitamin B12 intake (OR = 1.00, 95% CI = 0.81–1.23; HR = 1.10, 95% CI = 0.85–1.42) (Fig. 2B–D).

Fig.2

Forest plot of effect sizes for vitamin B12 on cognition. Note: Odds ratios or hazard ratios and 95% CIs were calculated using the Mantel-Haenszel method, with a random-effects model used to pool data. Risk ratio or hazard ratio data are rounded to 2 decimal places.

Association between folate and cognition

Compared with a low folate level, a high folate level was associated with a 32% lower risk of cognitive decline in cross-sectional studies (OR = 0.68, 95% CI = 0.51–0.90) (Fig. 3A). No significant association was found in prospective studies that measured folate blood concentrations (OR = 0.89, 95% CI = 0.79–1.00) and folate intake (OR = 0.84, 95% CI = 0.52–1.36; HR = 0.64, 95% CI = 0.41–1.00) (Fig. 3B–D). Sensitivity analysis showed no significance of the association (OR = 0.96; 95% CI = 0.90–1.01) after excluding four studies [18 , 31] due to the moderate heterogeneity among the studies assessing folate blood concentrations.

Fig.3

Forest plot of effect sizes for folate and cognition. Note: Odds ratios or hazard ratios and 95% CIs were calculated using the Mantel-Haenszel method, with a random-effects model used to pool data. Risk ratio or hazard ratio data are rounded to 2 decimal places.

Fig.4

Forest plot of effect sizes for vitamin B6 and cognition. Note: Odds ratios or hazard ratios and 95% CIs were calculated using the Mantel-Haenszel method, with a random-effects model used to pool data. Risk ratio or hazard ratio data are rounded to 2 decimal places.

Association between vitamin B6 and cognition

No significant association was found between vitamin B6 and a higher risk of dementia or cognitive impairment in cross-sectional studies assessing blood concentrations (OR = 1.09, 95% CI = 1.00–1.18) and prospective studies assessing blood concentrations (HR = 0.63, 95% CI = 0.33–1.22) or intake (OR = 0.61, 95% CI = 0.32–1.17; HR = 1.00, 95% CI = 0.73–1.37) (Fig. 4A–D). The results of the meta-analysis were also nonsignificant, and the results remained similar in the sensitivity analysis (HR = 0.85, 95% CI = 0.72–1.01) after excluding one study [28] due to heterogeneity.

DISCUSSION

Our study demonstrated that the blood concentration or dietary intake levels of vitamin B12, folate, and vitamin B6, were not significantly associated with a lower risk of dementia in older adults in population-based prospective studies. However, these measures showed some extent of significant association in cross-sectional studies. To our knowledge, this is the first study to evaluate the association between individual B vitamins and middle-life (45–75 years old, only one study) and late-life (over 60 years old) cognition in a population. A previous meta-analysis only focused on compound B vitamins [11].

Vitamin B12 deficiency can cause many neurological diseases, such as myelopathy and neuropathy [38]. Cross-sectional studies showed significant associations between low blood vitamin B12 levels and lower scores on cognitive tests performed among elderly individuals [39 –42]. On the other hand, the prospective study conducted by Clarke et al. [30] found that there was no association between cognitive decline (assessed with MMSE scores) and lower vitamin B12 levels. Previous studies have postulated that possessing the APOE ɛ4 allele in combination with other factors, such as level of education or B vitamin deficiencies, might increase the risk of dementia [43, 44]. APOE is an aggravating factor of the association between homocysteine and dementia [45]. Therefore, the differences in the results of those studies may be due to the interaction between vitamin B12 and the APOE ɛ4 allele.

Three prospective epidemiological studies have reported associations between a lower risk of cognitive decline and higher dietary folate [22 , 46], but with inconsistent findings. Studies have shown that in participants with low vitamin B12 status, higher folate intake was not associated with cognitive function [20, 37], or that higher folic acid intake may have been related to a higher risk of cognitive impairment [47]. Additionally, findings have also been inconsistent in studies measuring blood concentrations. Kado et al. [25] found that individuals with serum folate in the bottom quartile were associated with a 7-year decline in cognitive function in adults 70 years or older. Some published studies [48] have reported neutral or harmful interactions between folate and vitamin B12 status and cognitive decline risk. Moreover, prevention trials have been inconclusive to date [49]. Durga et al. [50] found that folic acid supplementation for 3 years significantly improved domains of cognitive function that tend to decline with age. However, the participants they studied had high plasma total homocysteine concentrations and were vitamin B12-replete individuals and, thus, may not be representative of community-dwelling residents. A recent meta-analysis by Wald and colleagues [51] reviewed nine randomized clinical trials of folic acid supplementation and did not find any significant protective effect of the supplementation on cognitive decline.

Lefevre et al. [36] found that the intake of vitamin B6 was not associated with the risk of cognitive decline in community-dwelling individuals. In contrast, Hughes et al. [28] performed a prospective study that concluded that low vitamin B6 status and dietary intake might be associated with a reduced risk of cognitive decline in older adults. However, in Hughes’ study, some potential confounding factors such as alcohol and tobacco consumption, diabetes, history of cardiovascular diseases, and hypertension, were not adequately controlled for, and these confounders may have affected the conclusion. On the other hand, some articles have emphasized the potential positive effects of vitamin B6 from the perspective of metabolic mechanisms [52, 53]. Vitamin B6 has a crucial role in the synthesis of a variety of neurotransmitters, including dopamine and serotonin [54] and higher vitamin B6 intake has been associated with a greater volume of grey matter [53]. However, there is no evidence to support a beneficial effect of vitamin B6 on cognitive function in older adults with normal vitamin B6 blood levels [55].

A previous meta-analysis indicated that compound B vitamin tablet supplementation showed no obvious cognitive benefit in randomized controlled trials (RCTs) [10]. These trials vary greatly in the population sampled, study quality, and duration of treatment, thereby making it difficult to draw firm conclusions. There was an RCT [56] that included 168 adults (>70 years) with mild cognitive impairment who were either assigned to a placebo group or a treatment group (daily dose of 0.8 mg folic acid, 0.5 mg vitamin B12, and 20 mg vitamin B6) and followed for 2 years. This RCT reported that brain atrophy was 53% slower in the treatment group than in the placebo group, but only in the patients with tHcy concentrations >13 mmol/L at baseline, which is not representative of a community population. For healthy older adults, multivitamin supplements may increase their blood concentration of biomarkers, e.g., vitamin B12, which is relevant to white matter hyperintensities [57]. However, these biomarker changes were not accompanied by improved cognitive function [58]. A meta-analysis showed that there was no significant effect of taking B vitamins or antioxidant vitamins on global cognitive function in RCTs [12].

The mechanism of the relationship between B vitamins and cognitive function is unclear. One possible mechanism involves the role of vitamin B12, B6, and folate in the metabolism of total plasma homocysteine (tHcy). Hyperhomocysteinemia has been reported in many studies to be associated with an increased risk of cognitive impairment [59 –61]. Supplementation with B vitamins can reliably decrease the plasma level of tHcy [62]. In the selected studies, the intake of B vitamins was measured by a specific food frequency questionnaire (FFQ) [23, 36]. Vitamin B6 blood concentrations were assessed by measuring PLP or pyridoxal-5-phosphate levels in the blood by high-performance liquid chromatography [28 , 63]. Folate (vitamin B9) levels were preferentially determined through the measurement of folate in red blood cells [38, 64]. Serum vitamin B12 was assessed by transcobalamin saturation and holotranscobalamin concentrations [38 , 66]. In a population with MCI, the accelerated rate of brain atrophy in the elderly individuals could be slowed by treatment with homocysteine-lowering B vitamins [56, 67]. However, evidence from a meta-analysis indicated that although elevated tHcy levels were associated with a higher risk of cognitive impairment and dementia, available evidence from randomized controlled trials showed no significant benefit for reducing the risk of dementia by using B vitamins to lower tHcy in community-dwelling older adults [10]. Additionally, both vitamin B6 and folate are involved in the synthesis of several key neurotransmitters, and folate deficiency has been related to oxidative stress and DNA damage in neurons [68, 69]. However, one study showed that a positive association with cortical folding was detectable in a population taking supplemental B vitamins, but cognitive function did not improve [55]. The uncertain mechanism by which B vitamins affect cognition may potentially explain the lack of association between the concentrations or intake of vitamin B12, folate, or vitamin B6 and cognition in the current meta-analysis.

Our study has several limitations. First, the included studies differed in neuropsychological tests and diversity in categorizing low (ranging from <150 to <308 pmol/L) and high (ranging from ≥150 to ≥522 pmol/L) vitamin B12 levels. Some studies also had marginally unequal sample sizes between low and high B vitamin categories. After excluding these studies that introduced heterogeneity in post hoc sensitivity analyses, the heterogeneity among the studies was lower, and B vitamins were not associated with a benefit for slowing cognitive decline. Therefore, it seems unlikely that this meta-analysis missed a potential beneficial association between B vitamins and any outcome analyzed due to inappropriate pooling of overly heterogeneous studies. Second, we only studied the relationship between B vitamins and global cognition or dementia incidence. However, B vitamins may have potential effects in specific domains of cognition. Due to the limitation of the number of articles, we did not analyze these associations. Third, we used both global cognition and dementia incidence simultaneously, which may have introduced bias, but the results remained similar after excluding eight studies measuring dementia incidence. Fourth, we did not consider the interactions among different B vitamins, because few studies reported such interactions. Fifth, we did not include RCTs because there are not enough intervention studies that met our inclusion criteria. Additionally, most intervention studies have focused on the effects of complex B vitamin supplements on the risk of dementia, and the content of B vitamins in each supplement was not consistent. Our study focuses on the independent effect of particular B vitamins on cognitive function. Sixth, the relationship between B vitamins and cognitive decline may be more evident in high-risk populations (such as older adults in the process of cognitive decline and those who have low B vitamin status). However, there were not enough studies that reported the relevant conclusions in these groups of people. Seventh, some studies have reported that other B vitamins, such as dietary vitamin B3 [70] and blood levels of vitamin B1 [55], may be related to AD and age-related cognitive decline. However, due to the limited evidence from observational studies, this study focused on the effects of B12, B6, and folic acid on cognitive decline. The role of other B vitamins needs further exploration before we can draw conclusions. Eighth, the research object of this study is the elderly population in the community. Few people have severe B vitamin deficiency, and most malnourished people are sub-optimal vitamin status. Therefore, the conclusion of this study may not be applicable to patients with severe B vitamin deficiency. Last, we did not exclude prospective studies with cognitive impaired participants or dementia at baseline, and the possibility that this had an influence cannot be disregarded.

Conclusion

Available evidence from observational population-based studies shows no significant association between vitamin B12, folate, or vitamin B6 and cognitive decline or dementia. Observational studies and RCTs with larger sample sizes and longer follow-up times are needed to provide solid evidence of the causal relationship, especially for other B vitamins.

Footnotes

ACKNOWLEDGMENTS

This work was supported by grants from National Natural Science Foundation of China (81773513), Shanghai Municipal Science and Technology Major Project (2018SHZDZX03), ZHANGJIANG LAB, Scientific Research Plan Project of Shanghai Science and Technology Committee (17411950701, 17411950106), and the National Project of Chronic Disease (2016YFC1306400).

Authors’ disclosures available online ().

The supplementary material is available in the electronic version of this article: .

References

Jack

, Knopman

, Jagust

, Petersen

, Weiner

, Aisen

, Shaw

, Vemuri

, Wiste

, Weigand

, Lesnick

, Pankratz

, Donohue

, Trojanowski

(2013) Tracking pathophysiological processes in Alzheimer’s disease: An updated hypothetical model of dynamic biomarkers. Lancet Neurol 12, 207–216.

Rege

, Geetha

, Broderick

, Babu

(2017) Can diet and physical activity limit Alzheimer’s disease risk? Curr Alzheimer Res 14, 76–93.

Monti

, Moulton

, Cohen

(2015) The role of nutrition on cognition and brain health in ageing: A targeted approach. Nutr Res Rev 28, 167–180.

Gustafson

, Clare

, Scarmeas

, Shah

, Sijben

, Yaffe

, Zhu

(2015) New perspectives on Alzheimer’s disease and nutrition. J Alzheimers Dis 46, 1111–1127.

Gillette-Guyonnet

, Secher

, Vellas

(2013) Nutrition and neurodegeneration: Epidemiological evidence and challenges for future research. Br J Clin Pharmacol 75, 738–755.

Ferry

, Coley

, Andrieu

, Bonhomme

, Caubere

, Cesari

, Gautry

, Garcia

, Hugonot

, Mansuy

, Pahor

, Pariente

, Ritz

, Salva

, Sijben

, Wieggers

, Ythier-Moury

, Zaim

, Zetlaoui

, Vellas

(2013) How to design nutritional intervention trials to slow cognitive decline in apparently healthy populations and apply for efficacy claims: A statement from the International Academy on Nutrition and Aging Task Force. J Nutr Health Aging 17, 619–623.

, Wu

(2018) Detecting spatiotemporal clusters of dementia mortality in the United States, 2000-2010. Spat Spatiotemporal Epidemiol 27, 11–20.

APA Work Group on Alzheimer’s Disease and other Dementias, Rabins

, Blacker

, Rovner

, Rummans

, Schneider

, Tariot

, Blass

; Steering Committee on Practice Guidelines, McIntyre

, Charles

, Anzia

, Cook

, Finnerty

, Johnson

, Nininger

, Schneidman

, Summergrad

, Woods

, Berger

, Cross

, Brandt

, Margolis

, Shemo

, Blinder

, Duncan

, Barnovitz

, Carino

, Freyberg

, Gray

, Tonnu

, Kunkle

, Albert

, Craig

, Regier

, Fochtmann

(2007) American Psychiatric Association practice guideline for the treatment of patients with Alzheimer’s disease and other dementias. Second edition. Am J Psychiatry 164(12 Suppl), 5–56.

Agronin

(2014) Alzheimer’s Disease and Other Dementias: A Practical Guide, Routledge, New York. .

10.

Ford

, Almeida

(2019) Effect of vitamin B supplementation on cognitive function in the elderly: A systematic review and meta-analysis. }. Drugs Aging 36, 419–434.

11.

Cao

, Tan

, Wang

, Jiang

, Zhu

, Lu

, Tan

, Yu

(2016) Dietary patterns and risk of dementia: A systematic review and meta-analysis of cohort studies. Mol Neurobiol 53, 6144–6154.

12.

Jia

, McNeill

, Avenell

(2008) Does taking vitamin, mineral and fatty acid supplements prevent cognitive decline? A systematic review of randomized controlled trials. J Hum Nutr Diet 21, 317–336.

13.

Moher

, Liberati

, Tetzlaff

, Altman

; PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 6, e1000097.

14.

Rajasekhar

, Lottenberg

, Liu

, Ang

(2011) Pulmonary embolism prophylaxis with inferior vena cava filters in trauma patients: A systematic review using the meta-analysis of observational studies in epidemiology (MOOSE) guidelines. J Thromb Thrombolysis 32, 40–46.

15.

Annweiler

, Montero-Odasso

, Llewellyn

, Richard-Devantoy

, Duque

, Beauchet

(2013) Meta-analysis of memory and executive dysfunctions in relation to vitamin D. J Alzheimers Dis 37, 147–171.

16.

Feller

, Snel

, Moutzouri

, Bauer

, de Montmollin

, Aujesky

, Ford

, Gussekloo

, Kearney

, Mooijaart

, Quinn

, Stott

, Westendorp

, Rodondi

, Dekkers

(2018) Association of thyroid hormone therapy with quality of life and thyroid-related symptoms in patients with subclinical hypothyroidism. JAMA 320, 1349.

17.

Mendonca

, Granic

, Mathers

, Martin-Ruiz

, Wesnes

, Seal

, Jagger

, Hill

(2017) One-carbon metabolism biomarkers and cognitive decline in the very old: The newcastle 85+study. J Am Med Dir Assoc 18, 806.e19–806.e27.

18.

Maxwell

, Hogan

, Ebly

(2002) Serum folate levels and subsequent adverse cerebrovascular outcomes in elderly persons. Dement Geriatr Cogn Disord 13, 225–234.

19.

Palacios

, Scott

, Sahasrabudhe

, Gao

, Tucker

(2019) Lower plasma vitamin B-6 is associated with 2-year cognitive decline in the Boston Puerto Rican health study. J Nutr 149, 635–641.

20.

Nelson

, Wengreen

, Munger

, Corcoran

(2009) Dietary folate, vitamin B-12, vitamin B-6 and incident Alzheimer’s disease: The cache county memory, health and aging study. J Nutr Health Aging 13, 899–905.

21.

Vercambre

, Boutron-Ruault

, Ritchie

, Clavel-Chapelon

, Berr

(2009) Long-term association of food and nutrient intakes with cognitive and functional decline: A 13-year follow-up study of elderly French women. Br J Nutr 102, 419–427.

22.

Luchsinger

, Tang

, Miller

, Green

, Mayeux

(2007) Relation of higher folate intake to lower risk of Alzheimer disease in the elderly. Arch Neurol 64, 86–92.

23.

Agnew-Blais

, Wassertheil-Smoller

, Kang

, Hogan

, Coker

, Snetselaar

, Smoller

(2015) Folate, vitamin B-6, and vitamin B-12 intake and mild cognitive impairment and probable dementia in the Women’s Health Initiative Memory Study. J Acad Nutr Diet 115, 231–241.

24.

Fischer

, Zehetmayer

, Jungwirth

, Weissgram

, Krampla

, Hinterberger

, Torma

, Rainer

, Huber

, Hoenigschnabl

, Gelpi

, Bauer

, Leitha

, Bauer

, Tragl

(2008) Risk factors for Alzheimer dementia in a community-based birth cohort at the age of 75 years. Dement Geriatr Cogn Disord 25, 501–507.

25.

Kado

, Karlamangla

, Huang

, Troen

, Rowe

, Selhub

, Seeman

(2005) Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging. Am J Med 118, 161–167.

26.

Castillo-Lancellotti

, Margozzini

, Valdivia

, Padilla

, Uauy

, Rozowski

, Tur

(2015) Serum folate, vitamin B12 and cognitive impairment in Chilean older adults. Public Health Nutr 18, 2600–2608.

27.

Ramos

, Allen

, Mungas

, Jagust

, Haan

, Green

, Miller

(2005) Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr 82, 1346–1352.

28.

Hughes

, Ward

, Tracey

, Hoey

, Molloy

, Pentieva

, McNulty

(2017) B-vitamin intake and biomarker status in relation to cognitive decline in healthy older adults in a 4-year follow-up study. Nutrients 9, 53.

29.

Lildballe

, Fedosov

, Sherliker

, Hin

, Clarke

, Nexo

(2011) Association of cognitive impairment with combinations of vitamin B(1)(2)-related parameters. Clin Chem 57, 1436–1443.

30.

Clarke

, Sherliker

, Hin

, Molloy

, Nexo

, Ueland

, Emmens

, Scott

, Evans

(2008) Folate and vitamin B12 status in relation to cognitive impairment and anaemia in the setting of voluntary fortification in the UK. Br J Nutr 100, 1054–1059.

31.

Wang

, Wahlin

, Basun

, Fastbom

, Winblad

, Fratiglioni

(2001) Vitamin B(12) and folate in relation to the development of Alzheimer’s disease. Neurology 56, 1188–1194.

32.

Hooshmand

, Solomon

, Kareholt

, Rusanen

, Hanninen

, Leiviska

, Winblad

, Laatikainen

, Soininen

, Kivipelto

(2012) Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: A longitudinal study. J Intern Med 271, 204–212.

33.

Brown

, Huang

, Karlamangla

, Seeman

, Kado

(2011) Do the effects of APOE-epsilon4 on cognitive function and decline depend upon vitamin status? MacArthur Studies of Successful Aging. J Nutr Health Aging 15, 196–201.

34.

Hin

, Clarke

, Sherliker

, Atoyebi

, Emmens

, Birks

, Schneede

, Ueland

, Nexo

, Scott

, Molloy

, Donaghy

, Frost

, Evans

(2006) Clinical relevance of low serum vitamin B12 concentrations in older people: The Banbury B12 study. Age Ageing 35, 416–422.

35.

Kim

, Choi

, Nam

, Kim

, Oh

, Yang

(2019) Cognitive impairment is associated with elevated serum homocysteine levels among older adults. Eur J Nutr 58, 399–408.

36.

Lefevre-Arbogast

, Feart

, Dartigues

, Helmer

, Letenneur

, Samieri

(2016) Dietary B vitamins and a 10-year risk of dementia in older persons. Nutrients 8, 761.

37.

Morris

, Evans

, Schneider

, Tangney

, Bienias

, Aggarwal

(2006) Dietary folate and vitamins B-12 and B-6 not associated with incident Alzheimer’s disease. J Alzheimers Dis 9, 435–443.

38.

Sechi

, Sechi

, Fois

, Kumar

(2016) Advances in clinical determinants and neurological manifestations of B vitamin deficiency in adults. Nutr Rev 74, 281–300.

39.

Clarke

, Birks

, Nexo

, Ueland

, Schneede

, Scott

, Molloy

, Evans

(2007) Low vitamin B-12 status and risk of cognitive decline in older adults. Am J Clin Nutr 86, 1384–1391.

40.

Daviglus

, Plassman

, Pirzada

, Bell

, Bowen

, Burke

, Connolly

, Dunbar-Jacob

, Granieri

, McGarry

, Patel

, Trevisan

, Williams

(2011) Risk factors and preventive interventions for Alzheimer disease: State of the science. Arch Neurol 68, 1185–1190.

41.

den Elzen

, van der Weele

, Gussekloo

, Westendorp

, Assendelft

(2010) Subnormal vitamin B12 concentrations and anaemia in older people: A systematic review. BMC Geriatr 10, 42.

42.

Dangour

, Allen

, Clarke

, Elbourne

, Fasey

, Fletcher

, Letley

, Richards

, Whyte

, Mills

, Uauy

(2011) A randomised controlled trial investigating the effect of vitamin B12 supplementation on neurological function in healthy older people: The Older People and Enhanced Neurological function (OPEN) study protocol [ISRCTN54195799]. Nutr J 10, 22.

43.

Seeman

, Huang

, Bretsky

, Crimmins

, Launer

, Guralnik

(2005) Education and APOE-e4 in longitudinal cognitive decline: MacArthur Studies of Successful Aging. , P74-P. J Gerontol B Psychol Sci Soc Sci 60, 83.

44.

Silva

, Albers

, Santana

, Vicente

, Martins

, Verdelho

, Guerreiro

, De-Mendonca

(2013) Do MCI patients with vitamin B12 deficiency have distinctive cognitive deficits? . BMC Res Notes 6, 357.

45.

Anello

, Guéant-Rodríguez

, Bosco

, Guéant

, Romano

, Namour

, Spada

, Caraci

, Pourié

, Daval

, Ferri

(2004) Homocysteine and methylenetetrahydrofolate reductase polymorphism in Alzheimer’s disease. Neuroreport 15, 859–861.

46.

Corrada

, Kawas

, Hallfrisch

, Muller

, Brookmeyer

(2005) Reduced risk of Alzheimer’s disease with high folate intake: The Baltimore Longitudinal Study of Aging. Alzheimers Dement 1, 11–18.

47.

Carney

, Canada

(2006) Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. Nutr Clin Pract 21, 188–189.

48.

Doets

, Ueland

, Tell

, Vollset

, Nygard

, Van’T

, De Groot

LCPG

, Nurk

, Refsum

, Smith

, Eussen

SJPM

(2014) Interactions between plasma concentrations of folate and markers of vitamin B12 status with cognitive performance in elderly people not exposed to folic acid fortification: The Hordaland Health Study. Br J Nutr 111, 1085–1095.

49.

Clarke

, Bennett

, Parish

, Lewington

, Skeaff

, Eussen

, Lewerin

, Stott

, Armitage

, Hankey

, Lonn

, Spence

, Galan

, de Groot

, Halsey

, Dangour

, Collins

, Grodstein

(2014) Effects of homocysteine lowering with B vitamins on cognitive aging: Meta-analysis of 11 trials with cognitive data on 22,000 individuals. Am J Clin Nutr 100, 657–666.

50.

Durga

, van Boxtel

, Schouten

, Kok

, Jolles

, Katan

, Verhoef

(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, 208–216.

51.

Wald

, Kasturiratne

, Simmonds

(2010) Effect of folic acid, with or without other B vitamins, on cognitive decline: Meta-analysis of randomized trials. Am J Med 123, 522–527.e2.

52.

Kirksey

, Morré

, Wasynczuk

(1990) Neuronal development in vitamin B6 deficiency. Ann N Y Acad Sci 585, 202–218.

53.

Erickson

, Suever

, Prakash

, Colcombe

, McAuley

, Kramer

(2008) Greater intake of vitamins B6 and B12 spares gray matter in healthy elderly: A voxel-based morphometry study. Brain Res 1199, 20–26.

54.

Karlsson

(1993) Neurotransmitter changes in aging and dementia. Nord J Psychiatry 47, 41–44.

55.

Jannusch

, Jockwitz

, Bidmon

, Moebus

, Amunts

, Caspers

(2017) A complex interplay of vitamin B1 and B6 metabolism with cognition, brain structure, and functional connectivity in older adults. Front Neurosci 11, 596.

56.

Smith

, Smith

, de Jager

, Whitbread

, Johnston

, Agacinski

, Oulhaj

, Bradley

, Jacoby

, Refsum

(2010) Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: A randomized controlled trial. PLoS One 5, e12244.

57.

de van der Schueren

MAE

, Lonterman-Monasch

, van der Flier

, Kramer

, Maier

, Muller

(2016) Malnutrition and risk of structural brain changes seen on magnetic resonance imaging in older adults. J Am Geriatr Soc 64, 2457–2463.

58.

Harris

, Macpherson

, Pipingas

(2015) Improved blood biomarkers but no cognitive effects from 16 weeks of multivitamin supplementation in healthy older adults. Nutrients 7, 3796–3812.

59.

Ford

, Flicker

, Hankey

, Norman

, van Bockxmeer

, Almeida

(2012) Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism and cognitive impairment: The health in men study. Mol Psychiatry 17, 559–566.

60.

Smith

(2008) The worldwide challenge of the dementias: A role for B vitamins and homocysteine? Food Nutr Bull 29, S143–S172.

61.

Van Dam

, Van Gool

(2009) Hyperhomocysteinemia and Alzheimer’s disease: A systematic review. Arch Gerontol Geriatr 48, 425–430.

62.

Parkins

, Poets

, O’Brien

, Stebbens

, Southall

(1998) Lowering blood homocysteine with folic acid based supplements: Meta-analysis of randomised trials. Homocysteine Lowering Trialists’ Collaboration. BMJ 316, 894–898.

63.

Clayton

(2006) B6-responsive disorders: A model of vitamin dependency. J Inherit Metab Dis 29, 317–326.

64.

Lucock

, Yates

(2002) Measurement of red blood cell methylfolate. Lancet 360, 1021–1022.

65.

Carmel

(2011) Biomarkers of cobalamin (vitamin B-12) status in the epidemiologic setting: A critical overview of context, applications, and performance characteristics of cobalamin, methylmalonic acid, and holotranscobalamin II. Am J Clin Nutr 94, 348S–358S.

66.

Heil

, de Jonge

, de Rotte

MCFJ

, van Wijnen

, Heiner-Fokkema

RMR

, Kobold

ACM

, Pekelharing

JMM

, Adriaansen

, Sanders

, Trienekens

, Rammeloo

, Lindemans

(2012) Screening for metabolic vitamin B12 deficiency by holotranscobalamin in patients suspected of vitamin B12 deficiency: A multicentre study. Ann Clin Biochem 49, 184–189.

67.

de Jager

, Oulhaj

, Jacoby

, Refsum

, Smith

(2012) Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: A randomized controlled trial. Int J Geriatr Psychiatry 27, 592–600.

68.

Malouf

, Grimley Evans

(2008) Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people. Cochrane Database Syst Rev 4, CD004514.

69.

Blount

, Mack

, Wehr

, MacGregor

, Hiatt

, Wang

, Wickramasinghe

, Everson

, Ames

(1997) Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage. Proc Natl Acad Sci U S A 94, 3290–3295.

70.

Morris

, Evans

, Bienias

, Scherr

, Tangney

, Hebert

, Bennett

, Wilson

, Aggarwal

(2004) Dietary niacin and the risk of incident Alzheimer’s disease and of cognitive decline. J Neurol Neurosurg Psychiatry 75, 1093–1099.