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Journal of Alzheimer’s Disease 46 (2015) 777–790 DOI 10.3233/JAD-150140 IOS Press
Associations between Homocysteine, Folic Acid, Vitamin B12 and Alzheimer’s Disease: Insights from Meta-Analyses Liang Shen and Hong-Fang Ji∗ Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Shandong University of Technology, Zibo, P. R. China
Accepted 20 March 2015
Abstract. The associations between homocysteine (Hcy), folic acid, and vitamin B12 and Alzheimer’s disease (AD) have gained much interest, while remaining controversial. We aim to perform meta-analyses to evaluate comprehensively: i) Hcy, folic acid, and vitamin B12 levels in AD patients in comparison with controls; and ii) the association between Hcy, folic acid, and vitamin B12 levels and risk of AD. A literature search was performed using Medline and Scopus databases. A total of 68 studies were identified and included in the meta-analyses. Stata 12.0 statistical software was used to perform the meta-analyses. First, AD patients may have higher level of Hcy, and lower levels of folate and vitamin B12 in plasma than controls. Further age-subgroup analysis showed no age effect for Hcy levels in plasma between AD patients and matched controls, while the differences in folate and vitamin B12 levels further enlarged with increased age. Second, data suggests that high Hcy and low folate levels may correlate with increased risk of AD occurrence. The comprehensive meta-analyses not only confirmed higher Hcy, lower folic acid, and vitamin B12 levels in AD patients than controls, but also implicated that high Hcy and low folic acid levels may be risk factors of AD. Further studies are encouraged to elucidate mechanisms linking these conditions. Keywords: Alzheimer’s disease, folic acid, homocysteine, meta-analysis, vitamin B12
INTRODUCTION Alzheimer’s disease (AD) is the most common cause of dementia and its clinical hallmark includes progressive loss of memory, cognitive function, and behavior impairment. With the accelerating population aging process the prevalence of AD is rising steadily [1, 2]. Although the etiology of AD is complicated, amyloid- (A) peptide fibril formation and deposition is thought to be a central pathogenic event of AD [3, 4]. Considerable effort has been devoted to discovering anti-AD agents targeting A, while many drugs failed in clinical trials. In recent years, increasing ∗ Correspondence to: Prof. Dr. Hong-Fang Ji, Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Shandong University of Technology, Zibo 255049, P. R. China. Tel.: +86 5332782220; E-mail: [email protected].
evidence suggests some modifiable risk factors playing a role in the pathogenesis of AD, and modifying these factors may be an alternative approach to delay or prevent risk of this disease [5, 6]. Homocysteine (Hcy) is a non-protein sulfur amino acid generated in the methionine cycle. Methionine synthesis from Hcy requires folic acid and vitamin B12 as cofactors. Accumulating evidence indicate higher Hcy and lower folic acid and vitamin B12 levels are prevalent in AD patients than healthy controls [7–10], while the associations between Hcy, folic acid, and vitamin B12 and AD remain to be comprehensively assessed at present. Therefore, in the current investigation, we aim to perform meta-analyses to evaluate Hcy, folic acid, and vitamin B12 levels in AD patients compared with healthy controls, and association between Hcy, folic acid, or vitamin B12 levels and risk of AD.
ISSN 1387-2877/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved
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METHODS Information retrieval We used the Medline and Scopus databases to perform a literature search up to January 2014 using the following key words: Alzheimer’s disease and homocysteine or folic acid or folate or vitamin B12 or cobalamin or vitamin B6. We also reviewed the reference lists and conference proceedings from retrieved articles in search of other relevant studies. Only references published in English were considered. Selection criteria The following criteria were employed to identify eligible studies. For the meta-analyses of Hcy, folic acid, and vitamin B12 levels in AD patients and healthy controls, studies must explicitly present the number of AD patients and controls, Hcy or folic acid or vitamin B12 mean levels, and standard deviations for both patients and controls. For the meta-analysis of the association between Hcy, folic acid, or vitamin B12 levels and risk of AD, studies must provide Hcy or folic acid, or vitamin B12 mean levels and standard deviations, adjusted relative risk (RR) and 95% confidence intervals (CI) for AD occurrence. The literature selection processes were detailed in Fig. 1. There were 768 references in total after removing duplicates. By excluding references not describing Hcy or folic acid or vitamin B12 data associated with AD, or non-original studies, 133 potentially relevant studies were obtained. Then, by considering the above inclusion criteria, 69 studies were then excluded for not presenting enough data to conduct meta-analyses, making a total of 64 eligible studies included in the present meta-analyses. Statistical analysis The extracted information from the eligible studies include the first author, year of publication, the number of cases and controls, the mean and standard deviation of Hcy, folic acid, or vitamin B12 levels, RR, and 95% CI of AD. The data were extracted independently by two investigators. We used the data to obtain: i) the standardized mean difference (SMD) and 95% CI concerning Hcy, folic acid, or vitamin B12 levels in AD patients and controls, or ii) RR and 95% CI concerning associations between Hcy, folic acid or vitamin B12 levels and risk of AD. A random-effect model was employed during the analyses. To assess the effect
of age on associations between Hcy, folic acid, or vitamin B12 and AD, the age-subgroup analyses were also conducted. Heterogeneity was examined employing Qtest and I2 score. All meta-analyses were accomplished using the Stata statistical software version 12.0 (Stata Corp LP, College Station, Texas). RESULTS Hcy level in AD patients A total of 40 studies covering 2,619 AD patients and 2,390 controls were included, among which, 37 studies were about plasma level, and 5 about cerebrospinal fluid (CSF) level of Hcy in patients and controls. Table 1 showed the first author, year of publication, mean ages, number of AD patients and controls, and Hcy levels of each study. Meta-analyses results were shown in Fig. 2A. Data suggests that AD patients may have higher levels of Hcy (summary SMD = 1.34, 95% CI = [1.06, 1.61]) than controls in plasma. There was statistically significant heterogeneity across the included studies (p = 0.000, I2 = 94.3%). Additionally, the obvious outliers in Fig. 2A were excluded and the rest were re-analyzed. The results also suggest that AD patients have higher levels of Hcy (summary SMD = 0.74, 95% CI = [0.58, 0.91]) than controls with decreased heterogeneity (p = 0.000, I2 = 83.3%) (Supplementary Figure 1A). Moreover, no significant difference in CSF Hcy level was found between AD patients and controls (summary SMD = 0.00, 95% CI = [−0.27, 0.28], Fig. 2A). Because the level of Hcy in CSF is rather low (about one hundred times lower than that in plasma) and the number of studies included is limited, more efforts were needed to obtain definite conclusion. To further explore the effect of age on Hcy levels in plasma in AD patients and controls, we performed subgroup analysis based on mean age of each study. There were 33 studies providing the mean age of patients and controls, which were divided into two age subgroups. 16 studies were divided into subgroup aged 74 years. According to the meta-analysis results of subgroup aged 74 years (summary SMD = 1.55, 95% CI = [1.08, 2.02]) (Fig. 2B), higher Hcy levels in AD patients than controls were found in both subgroups, and age exhibited no significant effect on this association. Further analysis after excluding outlier (summary SMD = 0.86, 95% CI = [0.57, 1.15] for subgroup aged < 74 years and summary SMD = 0.81, 95% CI = [0.52, 1.10] for subgroup aged >74 years)
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Fig. 1. Selection of studies for inclusion in the meta-analyses.
(Supplementary Figure 1B) also supported the above results. Folic acid and vitamin B12 levels in AD patients There were 36 studies covering a total of 2,596 AD patients and 2,842 controls included in the metaanalysis of folic acid level in AD patients and controls. Summary of these studies was shown in Table 2. As indicated in Fig. 3A, lower levels of folic acid were found both in plasma and in CSF (plasma summary SMD = −0.83, 95% CI = [−1.08, −0.57] with significant heterogeneity, and CSF summary SMD = −0.86, 95% CI = [−1.29, −0.43] with moderate heterogeneity) than controls. Parallel analysis after excluding three outliers about plasma folic acid levels (SMD = −0.55, 95% CI = [−0.76, −0.34]) (Supple-
mentary Figure 2A) also showed lower folic acid levels in AD patients and controls. In addition, a total of 30 studies regarding the plasma folic acid level presented the mean age of AD patients and controls, and 14 studies were divided into subgroup aged 74 years. Further age-subgroup analysis (Fig. 3B, group aged 74 years, summary SMD = −0.99, 95% CI = [−1.38, −0.59], I2 = 95.1%, p < 0.001) showed that with increased age the difference in folic acid level in plasma between patients and controls further enlarged. The re-analysis after excluding two outliers also showed that folic acid levels between patients and controls was subject to age (group aged 74 years, summary
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L. Shen and H.-F. Ji / Homocysteine and Alzheimer’s Disease Table 1 Summary of studies regarding Hcy levels (M/L) in AD patients and healthy controls
References
Plasma
CSF
Clarke 1998 [11] Leblhuber 2000 [12] Bottiglieri 2001 [13] Postiglione 2001 [14] Nilsson 2002 [15] Hogervorst 2002 [16] Miller 2002 [17] Selley 2002 [18] Mizrahi 2003 [19] Nagga 2003 [20] Religa 2003 [21] Selley 2003 [22] Gallucci 2004 [23] Genedani 2004 [24] Mizrahi 2004 [25] Quadri 2004 [26] Anello 2004 [27] Malaguarnera 2004 [28] Dominguez 2005 [29] Folin 2005 [30] Guidi 2005 [31] Asita De Silva 2005[32] Quadri 2005 [33] Annerbo 2006 [34] da Silva 2006 [35] Hernanaz 2007 [36] Selly 2007 [37] Koseoglu 2007 [38] Hagnelius 2008 [39] Lepara 2009 [40] Villa 2009 [41] Karimi 2009 [42] Linnebank 2010 [43] Smach 2011 [44] Czapski 2012 [45] Kim 2013 [46] Cervellati 2013 [47] Isobe 2005 [48] Serot 2005 [49] Popp 2009 [50] Linnebank 2010 [43] Smach 2011 [44]
Mean age (years) AD Control 73.2 ± 8.6 74.8 ± 8.8 71 ± 8.5 68 77.6 ± 6.4 73.9 ± 9 78 ± 7 77.4 – 74.7 ± 7.3 74.2 ± 6.3 76 76.9 ± 6.8 81.9 ± 1.7 – 79.1 ± 7.7 71.0 ± 6.6 71.3 ± 7.99 73.4 ± 5.4 80.3 ± 7.1 73 72 ± 6.8 78.9 ± 7.5 67.7 ± 7.2 73.8 ± 7.2 73.2 ± 7.1 71.9 78.3 ± 4.1 72.7 ± 10.1 79.96 ± 0.95 70.8 ± 7.8 – 73 ± 8 73.2 ± 6.9 – 79.4 ± 6.8 77.8 67.4 ± 5 77.7 73 ± 7.7 73 ± 8 73.2 ± 6.9
72.8 ± 8.8 70.2 ± 8.8 40.6 ± 14.6 68 79.9 ± 3.7 73.3 ± 7.7 75 ± 7 78.4 – 69 ± 5.8 71.2 ± 6 74.6 76.8 ± 9.7 81.1 ± 1.3 – 75.6 ± 8.5 69.5 ± 12.7 73.6 ± 4.14 73.9 ± 8.9 71.2 ± 9.7 71 70.5 ± 3.9 75.0 ± 8.5 63.6 ± 9.6 73.9 ± 6.5 73.5 ± 3.2 71.3 76.1 ± 3.9 64.1 ± 9.5 77.53 ± 0.96 74.7 ± 6.7 – 62 ± 10 73.5 ± 6.8 – 71.4 ± 6.6 79.3 65.7 ± 9.2 75 50.1 ± 16.8 62 ± 10 73.5 ± 6.8
SMD = −0.76, 95% CI = [−1.11, −0.42], Supplementary Figure 2B). A total of 34 studies, which covered 2,398 patients and 2,607 controls regarding the plasma vitamin B12 level in AD patients and controls (Table 3), were included. AD patients were also found to have lower vitamin B12 level than controls in plasma (summary SMD = −0.46, 95% CI = [−0.66, −0.26], I2 = 89.8%, p = 0.000, Fig. 4A; excluding two outlies summary SMD = −0.28, 95% CI = [−0.42, −0.14], I2 = 79.4%, p = 0.000, Supplementary Figure 3). Similar agesubgroup analysis (group aged 74 years
n AD
Control
164 19 48 74 94 137 32 27 64 47 99 25 137 22 75 74 180 30 29 79 97 23 111 32 42 25 29 51 42 30 20 51 60 70 182 100 89 17 38 54 60 70
108 19 14 74 36 277 22 25 64 101 100 25 42 22 155 55 181 30 19 24 23 21 79 59 50 44 26 40 73 30 18 49 60 30 90 121 48 16 22 98 60 30
Hcy levels (M /L) (Mean ± SD) AD Control 15.3 ± 8.4 17.8 ± 6.6 12.4 ± 11.1 20.9 ± 15.0 18.5 ± 9.3 14.7 ± 4.9 10.6 ± 2.0 21.05 ± 0.72 12.3 ± 4.3 16.5 ± 6.4 18.03 ± 9.94 23.52 ± 0.92 21.4 ± 10.6 22.5 ± 2.0 20.6 ± 8.7 16.8 ± 7.0 13.9 ± 9.2 23.5 ± 4.62 18.35 ± 4.2 21.01 ± 7.80 19.0 ± 0.8 13.3 ± 5.3 16.9 ± 7.3 18.4 ± 3.2 18.31 ± 7.6 14.8 ± 7.4 15.62 ± 0.68 14.2 ± 2.97 13.8 ± 4.6 16.15 ± 0.96 13.9 ± 2.47 20.4 ± 16.5 14.1 ± 4.3 12.9 ± 3.6 16.04 ± 7.53 11.9 ± 3.9 16.8 ± 1.7 0.1106 ± 0.0316 0.115 ± 0.062 0.07189 ± 0.04355 0.0719 ± 0.0435 0.187 ± 0.135
13.2 ± 4 13.8 ± 4.2 7.1 ± 2.9 11.8 ± 5.0 15.5 ± 3.7 12.8 ± 3.9 9.3 ± 2.2 16.01 ± 0.78 11.5 ± 3.7 12.9 ± 4.2 14.43 ± 4.48 19.04 ± 0.71 15.5 ± 5.2 16.3 ± 1.15 16.4 ± 6.5 14.6 ± 6.1 11.0 ± 5.3 10.8 ± 2.92 11.11 ± 1.88 15.79 ± 5.55 13.0 ± 0.7 8.3 ± 2.2 14.4 ± 6.1 16.8 ± 4.0 15.34 ± 5.4 10.4 ± 2.7 9.57 ± 0.84 10.3 ± 1.28 11.9 ± 3.6 12.60 ± 0.44 9.1 ± 2.82 14.5 ± 5 12.7 ± 5.4 11.6 ± 1.7 12.62 ± 3.94 10.8 ± 4.8 14.6 ± 1.4 0.0849 ± 0.0245 0.123 ± 0.089 0.07213 ± 0.0445 0.0776 ± 0.0526 0.216 ± 0.122
covering 15 studies, summary SMD = −0.59, 95% CI = [−0.93, −0.24]; I2 = 93.3%, p = 0.000, respectively) (Fig. 4B) found enlarged differences vitamin B12 levels in plasma between patients and controls.
Hcy level and risk of AD Nine studies covering 4,830 subjects regarding Hcy level and risk of AD were included and the summary of these studies was shown in Table 4. The overall RR was 1.77, 95% CI (1.37, 2.16) (Fig. 5), which suggests that elevated Hcy level may correlate with significantly increased risk of AD occurrence.
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Fig. 2. Pooled estimate of SMD and 95% CI of AD and homocysteine level. a) Overall SMD and 95% CI of AD and homocysteine level in plasma and CSF. b) Age-subgroup SMD and 95% CI of AD and homocysteine level in plasma according to age (74 years). Overall SMD is represented by squares, whose sizes are proportional to the sample size of the relative study. The whiskers represent the 95% CI. The diamond represents the pooled estimate based on the random effects model, with the center representing the point estimate and the width representing associated 95% CI.
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L. Shen and H.-F. Ji / Homocysteine and Alzheimer’s Disease Table 2 Summary of studies of folic acid levels (nM/L) in AD patients and healthy controls
References
Mean age (years) AD
Plasma
CSF
Parnetti 1992 [51] Regland 1992 [52] Joosten 1997 [53] Clarke 1998 [11] Leblhuber 2000 [12] Ravaglia 2000 [54] Bottiglieri 2001 [13] Postiglone 2001 [14] Hogervorst 2002 [55] Selley 2002 [18] Religa 2003 [21] Gallucci 2004 [23] Mizrahi 2004 [25] Quadri 2004 [26] Anello 2004 [27] Malaguarnera 2004 [28] Ravaglia 2004 [56] Irizarry 2005 [57] Dominguez 2005 [58] Quadri 2005 [33] Asita De Silva 2005[32] Annerbo 2006 [34] Lovati 2007 [59] Koseoglu 2007 [38] Hagnelius 2008 [39] Galimberti 2008 [60] Karimi 2009 [42] Villa 2009 [41] Linnebank 2010 [43] Agarwal 2010 [61] Morillas-Ruiz 2010 [62] Faux 2011 [63] Czapski 2012 [45] Kim 2013 [46] Serot 2001 [64] Selley 2002 [18] Hagnelius 2008 [39] Smach 2011 [44]
62.7 ± 1.2 64 ± 5 82.8 ± 4.9 73.2 ± 8.6 74.8 ± 8.8 – 71 ± 8.5 68 77 ± 8 77.4 74.2 ± 6.3 76.9 ± 6.8 – 79.1 ± 7.7 71.0 ± 6.6 71.3 ± 8.0 86.7 ± 5.4 75.9 ± 8.7 73.4 ± 5.4 78.9 ± 7.5 72 ± 6.8 67.7 ± 7.2 76.6 ± 7.5 78.3 ± 4.1 72.7 ± 10.1 78. 5 ± 4.6 – 70.8 ± 7.8 73 ± 8 65.03 ± 2.1 76.5 ± 3.5 78.4 ± 8.7 – 79.4 ± 6.8 75.9 ± 6.6 77.4 72.7 ± 10.1 73.2 ± 6.9
n
Control 72.1 ± 1.4 65 ± 7 79 ± 5.9 72.8 ± 8.8 70.2 ± 8.8 – 40.6 ± 14.6 68 76 ± 8 78.4 71.2 ± 6 76.8 ± 9.7 – 75.6 ± 8.5 69.5 ± 12.7 73.6 ± 4.1 86.7 ± 5.9 70.3 ± 9.8 73.9 ± 8.9 75.0 ± 8.5 70.5 ± 3.9 63.6 ± 9.6 67.6 ± 7.2 76.1 ± 3.9 64.1 ± 9.5 70.1 ± 3.0 – 74.7 ± 6.7 62 ± 10 48.65 ± 1.2 79 ± 4 70 ± 7 – 71.4 ± 6.6 72.7 ± 7 78.4 64.1 ± 9.5 73.5 ± 6.8
Folic acid level and risk of AD Six studies covering 2,070 subjects were included in the meta-analysis of association between folic acid level and risk of AD (Table 5). The RR was calculated to be 2.11, 95% CI (1.51, 2.71), which suggests that low folic acid level may correlate with increased risk of AD (Fig. 6). Vitamin B12 level and risk of AD As to vitamin B12, several studies have consistently reported that there was no significant association between vitamin B12 level and the risk of AD [11, 71, 73]. Despite the meta-analysis results suggesting that low vitamin B12 level may correlate with decreased
AD 52 23 52 164 19 34 48 74 66 27 99 137 75 74 180 30 51 145 29 111 23 29 108 51 42 29 51 20 60 32 52 205 204 100 30 8 42 70
Control 26 32 49 108 19 13 14 74 62 25 100 42 155 55 181 30 29 88 19 79 21 61 76 40 73 23 49 18 60 127 48 760 99 121 36 6 73 30
Folic acid levels (nM/L) (Mean ± SD) AD Control 9.5 ± 1.1 15.0 ± 10.0 7.9 ± 4.2 17.6 ± 10.7 10.0 ± 3.4 8.0 ± 0.5 8.0 ± 3.4 5.7 ± 2.1 15.9 ± 11.3 14.74 ± 0.82 19.3 ± 7.7 11.6 ± 6.1 4.3 ± 3.2 13.6 ± 5.6 14.3 ± 5.7 10.6 ± 3.16 11.1 ± 4.3 29.9 ± 21.3 17.87 ± 7.18 13.1 ± 5.9 15.9 ± 8.4 19.0 ± 14.0 8.2 ± 5.3 21.4 ± 4.4 11.2 ± 4.9 8.6 ± 2.8 14.5 ± 6.6 16.8 ± 4.7 15.62 ± 7.04 14.98 ± 2.61 21.8 ± 8.7 29.35 ± 1.01 19.82 ± 17.89 12.91 ± 10.6 18.71 ± 4.12 5.63 ± 0.46 26.3 ± 6.9 18.7 ± 2.4
14.1 ± 1.1 20.0 ± 18.0 8.6 ± 3.2 22.9 ± 10 14.3 ± 9.3 11.5 ± 1.2 12.1 ± 10 6.5 ± 3.2 24.9 ± 11.3 25.09 ± 0.94 17.1 ± 12.2 14.0 ± 11.1 4.8 ± 2.6 16.9 ± 5.8 15.7 ± 5.9 13.6 ± 3.18 16.57 ± 7.26 35.2 ± 32.9 29.57 ± 8.97 16.8 ± 5.5 19.7 ± 9.7 16.4 ± 10.8 15.6 ± 7.9 28.1 ± 3.4 13.4 ± 5.8 19.8 ± 6.2 15.9 ± 8.6 19.0 ± 4.1 14.05 ± 7.74 15.7 ± 2.67 28.8 ± 7.7 30.29 ± 0.46 19.43 ± 8.51 13.81 ± 9.2 22.56 ± 4.55 7.77 ± 1.13 30.4 ± 7.4 20.4 ± 1.7
risk of AD (overall RR, 0.79, 95% CI (0.36, 1.23) (Table 6 and Fig. 7), the association between vitamin B12 and AD risk was not conclusive and more studies were warranted on this issue. DISCUSSION AD is a progressive neurodegenerative disease and its etiology is found to involve multiple factors. In recent years, increasing interest has been attracted to the delay or prevention of cognitive decline or dementia by modifying some risk factors of AD. The present meta-analyses were designed to evaluate comprehensively the associations between AD and Hcy, folic acid, or vitamin B12 levels. Results suggest that AD patients
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Fig. 3. Pooled estimate of SMD and 95% CI of AD and folic acid level. a) Overall SMD and 95% CI of AD and folic acid level in plasma and CSF. b) Age-subgroup SMD and 95% CI of AD and folic acid level in plasma according to age (74 years). SMD is represented by squares, whose sizes are proportional to the sample size of the relative study. The whiskers represent the 95% CI. The diamond represents the pooled estimate based on the random effects model, with the center representing the point estimate and the width representing associated 95% CI.
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Fig. 4. Pooled estimate of SMD and 95% CI of AD and vitamin B12 level. a) Overall SMD and 95% CI of AD and vitamin B12 level in plasma and CSF. b) Age-subgroup SMD and 95% CI of AD and vitamin B12 level in plasma according to age (74 years). SMD is represented by squares, whose sizes are proportional to the sample size of the relative study. The whiskers represent the 95% CI. The diamond represents the pooled estimate based on the random effects model, with the center representing the point estimate and the width representing associated 95% CI.
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Table 3 Summary of studies regarding plasma vitamin B12 level (pM/L) in AD patients and healthy controls References
Mean age (years)
Parnetti 1992 [51] Regland 1992 [52] Kristensen 1993 [65] Joosten 1997[53] Clarke 1998 [11] Leblhuber 2000 [12] Ravaglia 2000 [54] Bottiglieri 2001 [13] Postiglone 2001 [14] Hogervorst 2002 [16] Miller 2002 [17] Selley 2002 [18] Religa 2003 [21] Anello 2004 [27] Malaguarnera 2004 [28] Gallucci 2004 [23] Mizrahi 2004 [25] Quadri 2004 [26] Ravaglia 2004 [56] Glaso 2004 [66] Dominguez 2005 [29] Asita De Silva 2005[32] Irizarry 2005 [57] Quadri 2005 [33] Annerbo 2006 [34] Koseoglu 2007 [38] Hagnelius 2008 [39] Karimi 2009 [42] Villa 2009 [41] Morillas-Ruiz 2010 [62] Linnebank 2010 [43] Faux 2011 [63] Czapski 2012 [45] Kim 2013 [46]
n
AD
Control
AD
Control
62.7 ± 1.2 64 ± 5 73.2 ± 1.8 82.8 ± 4.9 73.2 ± 8.6 74.8 ± 8.8 – 71 ± 8.5 68 77 ± 8 75 ± 7 77.4 74.2 ± 6.3 71.0 ± 6.6 71.3 ± 7.99 76.9 ± 6.8 – 79.1 ± 7.7 86.7 ± 5.4 – 73.35 ± 5.36 72 ± 6.8 75.9 ± 8.7 78.9 ± 7.5 67.7 ± 7.2 78.3 ± 4.1 72.7 ± 10.1 – 70.8 ± 7.8 76.5 ± 3.5 73 ± 8 78.4 ± 8.7 – 79.4 ± 6.8
72.1 ± 1.4 65 ± 7 73.4 ± 1.6 79 ± 5.9 72.8 ± 8.8 70.2 ± 8.8 – 40.6 ± 14.6 68 76 ± 8 78 ± 7 78.4 71.2 ± 6 69.5 ± 12.7 73.6 ± 4.14 76.8 ± 9.7 – 75.6 ± 8.5 86.7 ± 5.9 – 73.89 ± 8.87 70.5 ± 3.9 70.3 ± 9.8 75.0 ± 8.5 63.6 ± 9.6 76.1 ± 3.9 64.1 ± 9.5 – 74.7 ± 6.7 79 ± 4 62 ± 10 70 ± 7 – 71.4 ± 6.6
52 23 26 52 164 19 34 48 74 66 32 19 99 180 30 137 75 74 51 20 29 23 145 111 32 51 42 51 20 52 60 205 202 100
26 32 20 49 108 19 13 14 74 62 22 19 100 181 30 42 155 55 29 18 19 21 88 79 61 40 73 49 18 48 60 760 102 121
Vitamin B12 levels (pM/L) (Mean ± SD) AD Control 262 ± 150 267 ± 89 179 ± 92 210 ± 150 236 ± 112 260 ± 95 282 ± 24 353 ± 205 491 ± 144 261 ± 108 393.3 ± 207.3 253.6 ± 14.77 233.7 ± 102.9 278.0 ± 221.0 369.90 ± 77.03 277.3 ± 168.5 322.9 ± 136.0 281 ± 111 292 ± 96 350 ± 264 468 ± 218 357 ± 99 429 ± 220 272 ± 108 275 ± 103 207 ± 15.4 270 ± 125 288 ± 182 334 ± 126 454 ± 300 272 ± 192 298.8 ± 9.7 233.12 ± 111.1 435.01 ± 213.8
260 ± 117 280 ± 110 256 ± 103 210 ± 91 253 ± 100 283 ± 139 327 ± 69 481 ± 226 780 ± 211 346 ± 116 333.5 ± 149 322.4 ± 13.63 305.1 ± 178 283.0 ± 221.0 437.1 ± 5.18 353.9 ± 297.2 350.5 ± 175.3 278 ± 99 308 ± 127 435 ± 263 713 ± 256 365 ± 103 390 ± 179 275 ± 96 305 ± 112 287.5 ± 15.2 307 ± 128 211 ± 51 369 ± 199 441 ± 217 248 ± 103 300.2 ± 4.8 303.62 ± 134.3 492.9 ± 213.8
Table 4 Summary of studies regarding the association between Hcy level and the risk of AD
Table 5 Summary of studies regarding the association between folic acid level and the risk of AD
References
References
Folic acid level
Clarke 1998 [11] Wang 2001 [72] Maxwell 2002 [73] Ravaglia 2005 [70] Ravaglia 2006 [74] Kim 2013 [46]
≤17.1nM/L ≤10 nM/L ≤11.3 nM/L ≤11.8 nM/L ≤10.4 nM/L 14 M/L Miller 2002 [17] >12 M/L Seshadri 2002 [67] >13.1 M/L McIIroy 2002 [68] >13.3 M/L Luchsinger 2004 [69] >27.4 M/L Ravaglia 2005 [70] >15 M/L Haan 2007 [71] >13 M/L Cervellati 2013 [47] – Kim 2013 [46] >15 M/L
Number of individuals 272 54 1092 154 679 816 1405 137 221
Relative risk, 95% CI 2.0 [1.1, 3.4] 2.2 [0.31, 16] 1.8 [1.3, 2.5] 2.9 [1.0, 8.1] 1.3 [0.8, 2.3] 2.08 [1.15, 3.79] 2.39 [1.11, 5.16] 3.0 [0.86, 10.76] 2.49 [0.88, 7.08]
had higher levels of Hcy and lower levels of folic acid and vitamin B12 than healthy controls. The effect of age on theses associations were also explored. Moreover, high Hcy level may correlate with increased risk of AD occurrence, which supported the hypothesis that
Number of individuals
Relative risk, 95% CI
272 370 226 816 165 221
2.3 [1.4, 3.8] 1.7 [0.9, 3.2] 2.17 [0.85, 5.53] 1.98 [1.15, 3.40] 3.11 [1.49, 6.47] 2.70 [1.22, 5.98]
high Hcy is a risk factor for AD. Low level of folic acid may also correlate with increased risk of AD. There are multiple plausible explanations for the association between AD and Hcy level. First, concerning the causality of the association between Hcy and AD, Farkas et al. recently proposed that hyperhomocysteinemia represented both a cause and a consequence of neurodegeneration [75]. By testing
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Fig. 5. Relative risk and 95% CI from studies of high Hcy level and risk of AD.
Fig. 6. Relative risk and 95% CI from studies of low folic acid level and risk of AD. Table 6 Summary of the studies of the association between vitamin B12 levels and risk of AD References Wang 2001 [72] Ravaglia 2005 [70] Ravaglia 2006 [74]
Concentration Number of individuals ≤150 pM/L ≤251 pM/L ≤217 pM/L
370 816 165
Relative risk, 95% CI 1.6 [0.9, 2.8] 0.66 [0.40, 1.09] 0.6 [0.26, 1.39]
the effect of a hyperhomocysteinemia-inducing diet in ArcA transgenic AD mouse model, Farkas et al.
argued that hyperhomocysteinemia contributes to neurodegeneration and may also be caused by the neurodegenerative processes [75]. Second, oxidative stress has been widely accepted to play important role in the pathogenesis of AD [76, 77]. On one hand, Hcy elevation prompts the generation of various reactive oxygen free radicals which lead to increased oxidative stress [78, 79]. On the other hand, A oligomers can induce oxidative stress [80, 81], which can deplete 5methyltetrahydrofolate, and thereby increase plasma
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Fig. 7. Relative risk and 95% CI from studies of low vitamin B12 level and risk of AD.
homocysteine levels [82, 83]. Third, a high circulating level of Hcy is an independent risk factor for stroke [84]. As AD commonly co-occurs with stroke, Hcy and AD could be linked by stroke or microvascular diseases [7, 68]. Fourth, it was found that Hcy can influence the metabolism of A, whose aggregation is a central pathogenic event of AD [3, 4]. Hcy injection to rat brain results in a direct elevation of A level [85]. Additionally, both in vitro and in vivo studies reported the binding of exogenous Hcy to A, which facilitates its deposition through favoring the -sheet structure formation [86]. Fifth, Hcy elevation induces apoptosis in hippocampal neurons and form senile plaques and neurofibrillary tangles [87]. Sixth, Hcy elevation can promote the atrophy of key brain regions related to the process of AD and cognitive decline [9, 88, 89]. In addition, it is expected that there are other possible mechanisms underlying the association between AD and Hcy, which need to be elucidated by future studies. The associations between AD and folic acid or vitamin B12 may arise from two aspects. First, folic acid and vitamin B12 possess important biological activities, such as antioxidant potential to counteract oxidative stress, which is involved in the pathogenesis of AD. Second, vitamin B12 and folic acid are important mediators of Hcy levels, and thus, indirectly correlated with AD through multiple mechanisms discussed above.
the large number of subjects in included studies, and also different study quality among them. Second, we only included studies published in English. Third, there is limited number of eligible studies regarding Hcy, folic acid, or vitamin B12 levels in CSF in AD patients in comparison with controls, and the metaanalyses cannot provide definite results on this issue. Fourth, no studies regarding vitamin B6 in AD patients and controls were available to perform meta-analysis. Fifth, despite the comprehensive data included, due to the possible concurrent problems that trigger AD, the increased Hcy levels may not be directly associated with increased risk of AD.
CONCLUSION Our study provided comprehensive associations between AD and Hcy, folic acid, or vitamin B12 levels through meta-analyses. Data demonstrated that AD patients may have higher levels of Hcy, while lower levels of folic acid and vitamin B12 than healthy controls. High Hcy level and low folic acid level may correlate with increased risk of AD. The findings have potential implications for prevention and interventional treatment of AD. Future studies are needed to explore the causality between AD and Hcy, folic acid, or vitamin B12 levels and to examine the effects of folic acid and vitamin B supplementation in reducing risk of AD.
Limitations ACKNOWLEDGMENTS The major limitation of the present meta-analyses was the large between-study heterogeneity, which may arise from the gender, age, and ethnic differences of
This work was supported by the National Natural Science Foundation of China (Grant No. 31370745).
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Authors’ disclosures available online (http://j-alz. com/manuscript-disclosures/15-0140r1).
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SUPPLEMENTARY MATERIAL The supplementary material is available in the electronic version of this article: http://dx.doi.org/10. 3233/JAD-150140.
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Journal of Alzheimer’s Disease 46 (2015) 777–790 DOI 10.3233/JAD-150140 IOS Press
Associations between Homocysteine, Folic Acid, Vitamin B12 and Alzheimer’s Disease: Insights from Meta-Analyses Liang Shen and Hong-Fang Ji∗ Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Shandong University of Technology, Zibo, P. R. China
Accepted 20 March 2015
Abstract. The associations between homocysteine (Hcy), folic acid, and vitamin B12 and Alzheimer’s disease (AD) have gained much interest, while remaining controversial. We aim to perform meta-analyses to evaluate comprehensively: i) Hcy, folic acid, and vitamin B12 levels in AD patients in comparison with controls; and ii) the association between Hcy, folic acid, and vitamin B12 levels and risk of AD. A literature search was performed using Medline and Scopus databases. A total of 68 studies were identified and included in the meta-analyses. Stata 12.0 statistical software was used to perform the meta-analyses. First, AD patients may have higher level of Hcy, and lower levels of folate and vitamin B12 in plasma than controls. Further age-subgroup analysis showed no age effect for Hcy levels in plasma between AD patients and matched controls, while the differences in folate and vitamin B12 levels further enlarged with increased age. Second, data suggests that high Hcy and low folate levels may correlate with increased risk of AD occurrence. The comprehensive meta-analyses not only confirmed higher Hcy, lower folic acid, and vitamin B12 levels in AD patients than controls, but also implicated that high Hcy and low folic acid levels may be risk factors of AD. Further studies are encouraged to elucidate mechanisms linking these conditions. Keywords: Alzheimer’s disease, folic acid, homocysteine, meta-analysis, vitamin B12
INTRODUCTION Alzheimer’s disease (AD) is the most common cause of dementia and its clinical hallmark includes progressive loss of memory, cognitive function, and behavior impairment. With the accelerating population aging process the prevalence of AD is rising steadily [1, 2]. Although the etiology of AD is complicated, amyloid- (A) peptide fibril formation and deposition is thought to be a central pathogenic event of AD [3, 4]. Considerable effort has been devoted to discovering anti-AD agents targeting A, while many drugs failed in clinical trials. In recent years, increasing ∗ Correspondence to: Prof. Dr. Hong-Fang Ji, Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Shandong University of Technology, Zibo 255049, P. R. China. Tel.: +86 5332782220; E-mail: [email protected].
evidence suggests some modifiable risk factors playing a role in the pathogenesis of AD, and modifying these factors may be an alternative approach to delay or prevent risk of this disease [5, 6]. Homocysteine (Hcy) is a non-protein sulfur amino acid generated in the methionine cycle. Methionine synthesis from Hcy requires folic acid and vitamin B12 as cofactors. Accumulating evidence indicate higher Hcy and lower folic acid and vitamin B12 levels are prevalent in AD patients than healthy controls [7–10], while the associations between Hcy, folic acid, and vitamin B12 and AD remain to be comprehensively assessed at present. Therefore, in the current investigation, we aim to perform meta-analyses to evaluate Hcy, folic acid, and vitamin B12 levels in AD patients compared with healthy controls, and association between Hcy, folic acid, or vitamin B12 levels and risk of AD.
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METHODS Information retrieval We used the Medline and Scopus databases to perform a literature search up to January 2014 using the following key words: Alzheimer’s disease and homocysteine or folic acid or folate or vitamin B12 or cobalamin or vitamin B6. We also reviewed the reference lists and conference proceedings from retrieved articles in search of other relevant studies. Only references published in English were considered. Selection criteria The following criteria were employed to identify eligible studies. For the meta-analyses of Hcy, folic acid, and vitamin B12 levels in AD patients and healthy controls, studies must explicitly present the number of AD patients and controls, Hcy or folic acid or vitamin B12 mean levels, and standard deviations for both patients and controls. For the meta-analysis of the association between Hcy, folic acid, or vitamin B12 levels and risk of AD, studies must provide Hcy or folic acid, or vitamin B12 mean levels and standard deviations, adjusted relative risk (RR) and 95% confidence intervals (CI) for AD occurrence. The literature selection processes were detailed in Fig. 1. There were 768 references in total after removing duplicates. By excluding references not describing Hcy or folic acid or vitamin B12 data associated with AD, or non-original studies, 133 potentially relevant studies were obtained. Then, by considering the above inclusion criteria, 69 studies were then excluded for not presenting enough data to conduct meta-analyses, making a total of 64 eligible studies included in the present meta-analyses. Statistical analysis The extracted information from the eligible studies include the first author, year of publication, the number of cases and controls, the mean and standard deviation of Hcy, folic acid, or vitamin B12 levels, RR, and 95% CI of AD. The data were extracted independently by two investigators. We used the data to obtain: i) the standardized mean difference (SMD) and 95% CI concerning Hcy, folic acid, or vitamin B12 levels in AD patients and controls, or ii) RR and 95% CI concerning associations between Hcy, folic acid or vitamin B12 levels and risk of AD. A random-effect model was employed during the analyses. To assess the effect
of age on associations between Hcy, folic acid, or vitamin B12 and AD, the age-subgroup analyses were also conducted. Heterogeneity was examined employing Qtest and I2 score. All meta-analyses were accomplished using the Stata statistical software version 12.0 (Stata Corp LP, College Station, Texas). RESULTS Hcy level in AD patients A total of 40 studies covering 2,619 AD patients and 2,390 controls were included, among which, 37 studies were about plasma level, and 5 about cerebrospinal fluid (CSF) level of Hcy in patients and controls. Table 1 showed the first author, year of publication, mean ages, number of AD patients and controls, and Hcy levels of each study. Meta-analyses results were shown in Fig. 2A. Data suggests that AD patients may have higher levels of Hcy (summary SMD = 1.34, 95% CI = [1.06, 1.61]) than controls in plasma. There was statistically significant heterogeneity across the included studies (p = 0.000, I2 = 94.3%). Additionally, the obvious outliers in Fig. 2A were excluded and the rest were re-analyzed. The results also suggest that AD patients have higher levels of Hcy (summary SMD = 0.74, 95% CI = [0.58, 0.91]) than controls with decreased heterogeneity (p = 0.000, I2 = 83.3%) (Supplementary Figure 1A). Moreover, no significant difference in CSF Hcy level was found between AD patients and controls (summary SMD = 0.00, 95% CI = [−0.27, 0.28], Fig. 2A). Because the level of Hcy in CSF is rather low (about one hundred times lower than that in plasma) and the number of studies included is limited, more efforts were needed to obtain definite conclusion. To further explore the effect of age on Hcy levels in plasma in AD patients and controls, we performed subgroup analysis based on mean age of each study. There were 33 studies providing the mean age of patients and controls, which were divided into two age subgroups. 16 studies were divided into subgroup aged 74 years. According to the meta-analysis results of subgroup aged 74 years (summary SMD = 1.55, 95% CI = [1.08, 2.02]) (Fig. 2B), higher Hcy levels in AD patients than controls were found in both subgroups, and age exhibited no significant effect on this association. Further analysis after excluding outlier (summary SMD = 0.86, 95% CI = [0.57, 1.15] for subgroup aged < 74 years and summary SMD = 0.81, 95% CI = [0.52, 1.10] for subgroup aged >74 years)
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Fig. 1. Selection of studies for inclusion in the meta-analyses.
(Supplementary Figure 1B) also supported the above results. Folic acid and vitamin B12 levels in AD patients There were 36 studies covering a total of 2,596 AD patients and 2,842 controls included in the metaanalysis of folic acid level in AD patients and controls. Summary of these studies was shown in Table 2. As indicated in Fig. 3A, lower levels of folic acid were found both in plasma and in CSF (plasma summary SMD = −0.83, 95% CI = [−1.08, −0.57] with significant heterogeneity, and CSF summary SMD = −0.86, 95% CI = [−1.29, −0.43] with moderate heterogeneity) than controls. Parallel analysis after excluding three outliers about plasma folic acid levels (SMD = −0.55, 95% CI = [−0.76, −0.34]) (Supple-
mentary Figure 2A) also showed lower folic acid levels in AD patients and controls. In addition, a total of 30 studies regarding the plasma folic acid level presented the mean age of AD patients and controls, and 14 studies were divided into subgroup aged 74 years. Further age-subgroup analysis (Fig. 3B, group aged 74 years, summary SMD = −0.99, 95% CI = [−1.38, −0.59], I2 = 95.1%, p < 0.001) showed that with increased age the difference in folic acid level in plasma between patients and controls further enlarged. The re-analysis after excluding two outliers also showed that folic acid levels between patients and controls was subject to age (group aged 74 years, summary
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L. Shen and H.-F. Ji / Homocysteine and Alzheimer’s Disease Table 1 Summary of studies regarding Hcy levels (M/L) in AD patients and healthy controls
References
Plasma
CSF
Clarke 1998 [11] Leblhuber 2000 [12] Bottiglieri 2001 [13] Postiglione 2001 [14] Nilsson 2002 [15] Hogervorst 2002 [16] Miller 2002 [17] Selley 2002 [18] Mizrahi 2003 [19] Nagga 2003 [20] Religa 2003 [21] Selley 2003 [22] Gallucci 2004 [23] Genedani 2004 [24] Mizrahi 2004 [25] Quadri 2004 [26] Anello 2004 [27] Malaguarnera 2004 [28] Dominguez 2005 [29] Folin 2005 [30] Guidi 2005 [31] Asita De Silva 2005[32] Quadri 2005 [33] Annerbo 2006 [34] da Silva 2006 [35] Hernanaz 2007 [36] Selly 2007 [37] Koseoglu 2007 [38] Hagnelius 2008 [39] Lepara 2009 [40] Villa 2009 [41] Karimi 2009 [42] Linnebank 2010 [43] Smach 2011 [44] Czapski 2012 [45] Kim 2013 [46] Cervellati 2013 [47] Isobe 2005 [48] Serot 2005 [49] Popp 2009 [50] Linnebank 2010 [43] Smach 2011 [44]
Mean age (years) AD Control 73.2 ± 8.6 74.8 ± 8.8 71 ± 8.5 68 77.6 ± 6.4 73.9 ± 9 78 ± 7 77.4 – 74.7 ± 7.3 74.2 ± 6.3 76 76.9 ± 6.8 81.9 ± 1.7 – 79.1 ± 7.7 71.0 ± 6.6 71.3 ± 7.99 73.4 ± 5.4 80.3 ± 7.1 73 72 ± 6.8 78.9 ± 7.5 67.7 ± 7.2 73.8 ± 7.2 73.2 ± 7.1 71.9 78.3 ± 4.1 72.7 ± 10.1 79.96 ± 0.95 70.8 ± 7.8 – 73 ± 8 73.2 ± 6.9 – 79.4 ± 6.8 77.8 67.4 ± 5 77.7 73 ± 7.7 73 ± 8 73.2 ± 6.9
72.8 ± 8.8 70.2 ± 8.8 40.6 ± 14.6 68 79.9 ± 3.7 73.3 ± 7.7 75 ± 7 78.4 – 69 ± 5.8 71.2 ± 6 74.6 76.8 ± 9.7 81.1 ± 1.3 – 75.6 ± 8.5 69.5 ± 12.7 73.6 ± 4.14 73.9 ± 8.9 71.2 ± 9.7 71 70.5 ± 3.9 75.0 ± 8.5 63.6 ± 9.6 73.9 ± 6.5 73.5 ± 3.2 71.3 76.1 ± 3.9 64.1 ± 9.5 77.53 ± 0.96 74.7 ± 6.7 – 62 ± 10 73.5 ± 6.8 – 71.4 ± 6.6 79.3 65.7 ± 9.2 75 50.1 ± 16.8 62 ± 10 73.5 ± 6.8
SMD = −0.76, 95% CI = [−1.11, −0.42], Supplementary Figure 2B). A total of 34 studies, which covered 2,398 patients and 2,607 controls regarding the plasma vitamin B12 level in AD patients and controls (Table 3), were included. AD patients were also found to have lower vitamin B12 level than controls in plasma (summary SMD = −0.46, 95% CI = [−0.66, −0.26], I2 = 89.8%, p = 0.000, Fig. 4A; excluding two outlies summary SMD = −0.28, 95% CI = [−0.42, −0.14], I2 = 79.4%, p = 0.000, Supplementary Figure 3). Similar agesubgroup analysis (group aged 74 years
n AD
Control
164 19 48 74 94 137 32 27 64 47 99 25 137 22 75 74 180 30 29 79 97 23 111 32 42 25 29 51 42 30 20 51 60 70 182 100 89 17 38 54 60 70
108 19 14 74 36 277 22 25 64 101 100 25 42 22 155 55 181 30 19 24 23 21 79 59 50 44 26 40 73 30 18 49 60 30 90 121 48 16 22 98 60 30
Hcy levels (M /L) (Mean ± SD) AD Control 15.3 ± 8.4 17.8 ± 6.6 12.4 ± 11.1 20.9 ± 15.0 18.5 ± 9.3 14.7 ± 4.9 10.6 ± 2.0 21.05 ± 0.72 12.3 ± 4.3 16.5 ± 6.4 18.03 ± 9.94 23.52 ± 0.92 21.4 ± 10.6 22.5 ± 2.0 20.6 ± 8.7 16.8 ± 7.0 13.9 ± 9.2 23.5 ± 4.62 18.35 ± 4.2 21.01 ± 7.80 19.0 ± 0.8 13.3 ± 5.3 16.9 ± 7.3 18.4 ± 3.2 18.31 ± 7.6 14.8 ± 7.4 15.62 ± 0.68 14.2 ± 2.97 13.8 ± 4.6 16.15 ± 0.96 13.9 ± 2.47 20.4 ± 16.5 14.1 ± 4.3 12.9 ± 3.6 16.04 ± 7.53 11.9 ± 3.9 16.8 ± 1.7 0.1106 ± 0.0316 0.115 ± 0.062 0.07189 ± 0.04355 0.0719 ± 0.0435 0.187 ± 0.135
13.2 ± 4 13.8 ± 4.2 7.1 ± 2.9 11.8 ± 5.0 15.5 ± 3.7 12.8 ± 3.9 9.3 ± 2.2 16.01 ± 0.78 11.5 ± 3.7 12.9 ± 4.2 14.43 ± 4.48 19.04 ± 0.71 15.5 ± 5.2 16.3 ± 1.15 16.4 ± 6.5 14.6 ± 6.1 11.0 ± 5.3 10.8 ± 2.92 11.11 ± 1.88 15.79 ± 5.55 13.0 ± 0.7 8.3 ± 2.2 14.4 ± 6.1 16.8 ± 4.0 15.34 ± 5.4 10.4 ± 2.7 9.57 ± 0.84 10.3 ± 1.28 11.9 ± 3.6 12.60 ± 0.44 9.1 ± 2.82 14.5 ± 5 12.7 ± 5.4 11.6 ± 1.7 12.62 ± 3.94 10.8 ± 4.8 14.6 ± 1.4 0.0849 ± 0.0245 0.123 ± 0.089 0.07213 ± 0.0445 0.0776 ± 0.0526 0.216 ± 0.122
covering 15 studies, summary SMD = −0.59, 95% CI = [−0.93, −0.24]; I2 = 93.3%, p = 0.000, respectively) (Fig. 4B) found enlarged differences vitamin B12 levels in plasma between patients and controls.
Hcy level and risk of AD Nine studies covering 4,830 subjects regarding Hcy level and risk of AD were included and the summary of these studies was shown in Table 4. The overall RR was 1.77, 95% CI (1.37, 2.16) (Fig. 5), which suggests that elevated Hcy level may correlate with significantly increased risk of AD occurrence.
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Fig. 2. Pooled estimate of SMD and 95% CI of AD and homocysteine level. a) Overall SMD and 95% CI of AD and homocysteine level in plasma and CSF. b) Age-subgroup SMD and 95% CI of AD and homocysteine level in plasma according to age (74 years). Overall SMD is represented by squares, whose sizes are proportional to the sample size of the relative study. The whiskers represent the 95% CI. The diamond represents the pooled estimate based on the random effects model, with the center representing the point estimate and the width representing associated 95% CI.
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L. Shen and H.-F. Ji / Homocysteine and Alzheimer’s Disease Table 2 Summary of studies of folic acid levels (nM/L) in AD patients and healthy controls
References
Mean age (years) AD
Plasma
CSF
Parnetti 1992 [51] Regland 1992 [52] Joosten 1997 [53] Clarke 1998 [11] Leblhuber 2000 [12] Ravaglia 2000 [54] Bottiglieri 2001 [13] Postiglone 2001 [14] Hogervorst 2002 [55] Selley 2002 [18] Religa 2003 [21] Gallucci 2004 [23] Mizrahi 2004 [25] Quadri 2004 [26] Anello 2004 [27] Malaguarnera 2004 [28] Ravaglia 2004 [56] Irizarry 2005 [57] Dominguez 2005 [58] Quadri 2005 [33] Asita De Silva 2005[32] Annerbo 2006 [34] Lovati 2007 [59] Koseoglu 2007 [38] Hagnelius 2008 [39] Galimberti 2008 [60] Karimi 2009 [42] Villa 2009 [41] Linnebank 2010 [43] Agarwal 2010 [61] Morillas-Ruiz 2010 [62] Faux 2011 [63] Czapski 2012 [45] Kim 2013 [46] Serot 2001 [64] Selley 2002 [18] Hagnelius 2008 [39] Smach 2011 [44]
62.7 ± 1.2 64 ± 5 82.8 ± 4.9 73.2 ± 8.6 74.8 ± 8.8 – 71 ± 8.5 68 77 ± 8 77.4 74.2 ± 6.3 76.9 ± 6.8 – 79.1 ± 7.7 71.0 ± 6.6 71.3 ± 8.0 86.7 ± 5.4 75.9 ± 8.7 73.4 ± 5.4 78.9 ± 7.5 72 ± 6.8 67.7 ± 7.2 76.6 ± 7.5 78.3 ± 4.1 72.7 ± 10.1 78. 5 ± 4.6 – 70.8 ± 7.8 73 ± 8 65.03 ± 2.1 76.5 ± 3.5 78.4 ± 8.7 – 79.4 ± 6.8 75.9 ± 6.6 77.4 72.7 ± 10.1 73.2 ± 6.9
n
Control 72.1 ± 1.4 65 ± 7 79 ± 5.9 72.8 ± 8.8 70.2 ± 8.8 – 40.6 ± 14.6 68 76 ± 8 78.4 71.2 ± 6 76.8 ± 9.7 – 75.6 ± 8.5 69.5 ± 12.7 73.6 ± 4.1 86.7 ± 5.9 70.3 ± 9.8 73.9 ± 8.9 75.0 ± 8.5 70.5 ± 3.9 63.6 ± 9.6 67.6 ± 7.2 76.1 ± 3.9 64.1 ± 9.5 70.1 ± 3.0 – 74.7 ± 6.7 62 ± 10 48.65 ± 1.2 79 ± 4 70 ± 7 – 71.4 ± 6.6 72.7 ± 7 78.4 64.1 ± 9.5 73.5 ± 6.8
Folic acid level and risk of AD Six studies covering 2,070 subjects were included in the meta-analysis of association between folic acid level and risk of AD (Table 5). The RR was calculated to be 2.11, 95% CI (1.51, 2.71), which suggests that low folic acid level may correlate with increased risk of AD (Fig. 6). Vitamin B12 level and risk of AD As to vitamin B12, several studies have consistently reported that there was no significant association between vitamin B12 level and the risk of AD [11, 71, 73]. Despite the meta-analysis results suggesting that low vitamin B12 level may correlate with decreased
AD 52 23 52 164 19 34 48 74 66 27 99 137 75 74 180 30 51 145 29 111 23 29 108 51 42 29 51 20 60 32 52 205 204 100 30 8 42 70
Control 26 32 49 108 19 13 14 74 62 25 100 42 155 55 181 30 29 88 19 79 21 61 76 40 73 23 49 18 60 127 48 760 99 121 36 6 73 30
Folic acid levels (nM/L) (Mean ± SD) AD Control 9.5 ± 1.1 15.0 ± 10.0 7.9 ± 4.2 17.6 ± 10.7 10.0 ± 3.4 8.0 ± 0.5 8.0 ± 3.4 5.7 ± 2.1 15.9 ± 11.3 14.74 ± 0.82 19.3 ± 7.7 11.6 ± 6.1 4.3 ± 3.2 13.6 ± 5.6 14.3 ± 5.7 10.6 ± 3.16 11.1 ± 4.3 29.9 ± 21.3 17.87 ± 7.18 13.1 ± 5.9 15.9 ± 8.4 19.0 ± 14.0 8.2 ± 5.3 21.4 ± 4.4 11.2 ± 4.9 8.6 ± 2.8 14.5 ± 6.6 16.8 ± 4.7 15.62 ± 7.04 14.98 ± 2.61 21.8 ± 8.7 29.35 ± 1.01 19.82 ± 17.89 12.91 ± 10.6 18.71 ± 4.12 5.63 ± 0.46 26.3 ± 6.9 18.7 ± 2.4
14.1 ± 1.1 20.0 ± 18.0 8.6 ± 3.2 22.9 ± 10 14.3 ± 9.3 11.5 ± 1.2 12.1 ± 10 6.5 ± 3.2 24.9 ± 11.3 25.09 ± 0.94 17.1 ± 12.2 14.0 ± 11.1 4.8 ± 2.6 16.9 ± 5.8 15.7 ± 5.9 13.6 ± 3.18 16.57 ± 7.26 35.2 ± 32.9 29.57 ± 8.97 16.8 ± 5.5 19.7 ± 9.7 16.4 ± 10.8 15.6 ± 7.9 28.1 ± 3.4 13.4 ± 5.8 19.8 ± 6.2 15.9 ± 8.6 19.0 ± 4.1 14.05 ± 7.74 15.7 ± 2.67 28.8 ± 7.7 30.29 ± 0.46 19.43 ± 8.51 13.81 ± 9.2 22.56 ± 4.55 7.77 ± 1.13 30.4 ± 7.4 20.4 ± 1.7
risk of AD (overall RR, 0.79, 95% CI (0.36, 1.23) (Table 6 and Fig. 7), the association between vitamin B12 and AD risk was not conclusive and more studies were warranted on this issue. DISCUSSION AD is a progressive neurodegenerative disease and its etiology is found to involve multiple factors. In recent years, increasing interest has been attracted to the delay or prevention of cognitive decline or dementia by modifying some risk factors of AD. The present meta-analyses were designed to evaluate comprehensively the associations between AD and Hcy, folic acid, or vitamin B12 levels. Results suggest that AD patients
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Fig. 3. Pooled estimate of SMD and 95% CI of AD and folic acid level. a) Overall SMD and 95% CI of AD and folic acid level in plasma and CSF. b) Age-subgroup SMD and 95% CI of AD and folic acid level in plasma according to age (74 years). SMD is represented by squares, whose sizes are proportional to the sample size of the relative study. The whiskers represent the 95% CI. The diamond represents the pooled estimate based on the random effects model, with the center representing the point estimate and the width representing associated 95% CI.
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Fig. 4. Pooled estimate of SMD and 95% CI of AD and vitamin B12 level. a) Overall SMD and 95% CI of AD and vitamin B12 level in plasma and CSF. b) Age-subgroup SMD and 95% CI of AD and vitamin B12 level in plasma according to age (74 years). SMD is represented by squares, whose sizes are proportional to the sample size of the relative study. The whiskers represent the 95% CI. The diamond represents the pooled estimate based on the random effects model, with the center representing the point estimate and the width representing associated 95% CI.
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Table 3 Summary of studies regarding plasma vitamin B12 level (pM/L) in AD patients and healthy controls References
Mean age (years)
Parnetti 1992 [51] Regland 1992 [52] Kristensen 1993 [65] Joosten 1997[53] Clarke 1998 [11] Leblhuber 2000 [12] Ravaglia 2000 [54] Bottiglieri 2001 [13] Postiglone 2001 [14] Hogervorst 2002 [16] Miller 2002 [17] Selley 2002 [18] Religa 2003 [21] Anello 2004 [27] Malaguarnera 2004 [28] Gallucci 2004 [23] Mizrahi 2004 [25] Quadri 2004 [26] Ravaglia 2004 [56] Glaso 2004 [66] Dominguez 2005 [29] Asita De Silva 2005[32] Irizarry 2005 [57] Quadri 2005 [33] Annerbo 2006 [34] Koseoglu 2007 [38] Hagnelius 2008 [39] Karimi 2009 [42] Villa 2009 [41] Morillas-Ruiz 2010 [62] Linnebank 2010 [43] Faux 2011 [63] Czapski 2012 [45] Kim 2013 [46]
n
AD
Control
AD
Control
62.7 ± 1.2 64 ± 5 73.2 ± 1.8 82.8 ± 4.9 73.2 ± 8.6 74.8 ± 8.8 – 71 ± 8.5 68 77 ± 8 75 ± 7 77.4 74.2 ± 6.3 71.0 ± 6.6 71.3 ± 7.99 76.9 ± 6.8 – 79.1 ± 7.7 86.7 ± 5.4 – 73.35 ± 5.36 72 ± 6.8 75.9 ± 8.7 78.9 ± 7.5 67.7 ± 7.2 78.3 ± 4.1 72.7 ± 10.1 – 70.8 ± 7.8 76.5 ± 3.5 73 ± 8 78.4 ± 8.7 – 79.4 ± 6.8
72.1 ± 1.4 65 ± 7 73.4 ± 1.6 79 ± 5.9 72.8 ± 8.8 70.2 ± 8.8 – 40.6 ± 14.6 68 76 ± 8 78 ± 7 78.4 71.2 ± 6 69.5 ± 12.7 73.6 ± 4.14 76.8 ± 9.7 – 75.6 ± 8.5 86.7 ± 5.9 – 73.89 ± 8.87 70.5 ± 3.9 70.3 ± 9.8 75.0 ± 8.5 63.6 ± 9.6 76.1 ± 3.9 64.1 ± 9.5 – 74.7 ± 6.7 79 ± 4 62 ± 10 70 ± 7 – 71.4 ± 6.6
52 23 26 52 164 19 34 48 74 66 32 19 99 180 30 137 75 74 51 20 29 23 145 111 32 51 42 51 20 52 60 205 202 100
26 32 20 49 108 19 13 14 74 62 22 19 100 181 30 42 155 55 29 18 19 21 88 79 61 40 73 49 18 48 60 760 102 121
Vitamin B12 levels (pM/L) (Mean ± SD) AD Control 262 ± 150 267 ± 89 179 ± 92 210 ± 150 236 ± 112 260 ± 95 282 ± 24 353 ± 205 491 ± 144 261 ± 108 393.3 ± 207.3 253.6 ± 14.77 233.7 ± 102.9 278.0 ± 221.0 369.90 ± 77.03 277.3 ± 168.5 322.9 ± 136.0 281 ± 111 292 ± 96 350 ± 264 468 ± 218 357 ± 99 429 ± 220 272 ± 108 275 ± 103 207 ± 15.4 270 ± 125 288 ± 182 334 ± 126 454 ± 300 272 ± 192 298.8 ± 9.7 233.12 ± 111.1 435.01 ± 213.8
260 ± 117 280 ± 110 256 ± 103 210 ± 91 253 ± 100 283 ± 139 327 ± 69 481 ± 226 780 ± 211 346 ± 116 333.5 ± 149 322.4 ± 13.63 305.1 ± 178 283.0 ± 221.0 437.1 ± 5.18 353.9 ± 297.2 350.5 ± 175.3 278 ± 99 308 ± 127 435 ± 263 713 ± 256 365 ± 103 390 ± 179 275 ± 96 305 ± 112 287.5 ± 15.2 307 ± 128 211 ± 51 369 ± 199 441 ± 217 248 ± 103 300.2 ± 4.8 303.62 ± 134.3 492.9 ± 213.8
Table 4 Summary of studies regarding the association between Hcy level and the risk of AD
Table 5 Summary of studies regarding the association between folic acid level and the risk of AD
References
References
Folic acid level
Clarke 1998 [11] Wang 2001 [72] Maxwell 2002 [73] Ravaglia 2005 [70] Ravaglia 2006 [74] Kim 2013 [46]
≤17.1nM/L ≤10 nM/L ≤11.3 nM/L ≤11.8 nM/L ≤10.4 nM/L 14 M/L Miller 2002 [17] >12 M/L Seshadri 2002 [67] >13.1 M/L McIIroy 2002 [68] >13.3 M/L Luchsinger 2004 [69] >27.4 M/L Ravaglia 2005 [70] >15 M/L Haan 2007 [71] >13 M/L Cervellati 2013 [47] – Kim 2013 [46] >15 M/L
Number of individuals 272 54 1092 154 679 816 1405 137 221
Relative risk, 95% CI 2.0 [1.1, 3.4] 2.2 [0.31, 16] 1.8 [1.3, 2.5] 2.9 [1.0, 8.1] 1.3 [0.8, 2.3] 2.08 [1.15, 3.79] 2.39 [1.11, 5.16] 3.0 [0.86, 10.76] 2.49 [0.88, 7.08]
had higher levels of Hcy and lower levels of folic acid and vitamin B12 than healthy controls. The effect of age on theses associations were also explored. Moreover, high Hcy level may correlate with increased risk of AD occurrence, which supported the hypothesis that
Number of individuals
Relative risk, 95% CI
272 370 226 816 165 221
2.3 [1.4, 3.8] 1.7 [0.9, 3.2] 2.17 [0.85, 5.53] 1.98 [1.15, 3.40] 3.11 [1.49, 6.47] 2.70 [1.22, 5.98]
high Hcy is a risk factor for AD. Low level of folic acid may also correlate with increased risk of AD. There are multiple plausible explanations for the association between AD and Hcy level. First, concerning the causality of the association between Hcy and AD, Farkas et al. recently proposed that hyperhomocysteinemia represented both a cause and a consequence of neurodegeneration [75]. By testing
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Fig. 5. Relative risk and 95% CI from studies of high Hcy level and risk of AD.
Fig. 6. Relative risk and 95% CI from studies of low folic acid level and risk of AD. Table 6 Summary of the studies of the association between vitamin B12 levels and risk of AD References Wang 2001 [72] Ravaglia 2005 [70] Ravaglia 2006 [74]
Concentration Number of individuals ≤150 pM/L ≤251 pM/L ≤217 pM/L
370 816 165
Relative risk, 95% CI 1.6 [0.9, 2.8] 0.66 [0.40, 1.09] 0.6 [0.26, 1.39]
the effect of a hyperhomocysteinemia-inducing diet in ArcA transgenic AD mouse model, Farkas et al.
argued that hyperhomocysteinemia contributes to neurodegeneration and may also be caused by the neurodegenerative processes [75]. Second, oxidative stress has been widely accepted to play important role in the pathogenesis of AD [76, 77]. On one hand, Hcy elevation prompts the generation of various reactive oxygen free radicals which lead to increased oxidative stress [78, 79]. On the other hand, A oligomers can induce oxidative stress [80, 81], which can deplete 5methyltetrahydrofolate, and thereby increase plasma
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Fig. 7. Relative risk and 95% CI from studies of low vitamin B12 level and risk of AD.
homocysteine levels [82, 83]. Third, a high circulating level of Hcy is an independent risk factor for stroke [84]. As AD commonly co-occurs with stroke, Hcy and AD could be linked by stroke or microvascular diseases [7, 68]. Fourth, it was found that Hcy can influence the metabolism of A, whose aggregation is a central pathogenic event of AD [3, 4]. Hcy injection to rat brain results in a direct elevation of A level [85]. Additionally, both in vitro and in vivo studies reported the binding of exogenous Hcy to A, which facilitates its deposition through favoring the -sheet structure formation [86]. Fifth, Hcy elevation induces apoptosis in hippocampal neurons and form senile plaques and neurofibrillary tangles [87]. Sixth, Hcy elevation can promote the atrophy of key brain regions related to the process of AD and cognitive decline [9, 88, 89]. In addition, it is expected that there are other possible mechanisms underlying the association between AD and Hcy, which need to be elucidated by future studies. The associations between AD and folic acid or vitamin B12 may arise from two aspects. First, folic acid and vitamin B12 possess important biological activities, such as antioxidant potential to counteract oxidative stress, which is involved in the pathogenesis of AD. Second, vitamin B12 and folic acid are important mediators of Hcy levels, and thus, indirectly correlated with AD through multiple mechanisms discussed above.
the large number of subjects in included studies, and also different study quality among them. Second, we only included studies published in English. Third, there is limited number of eligible studies regarding Hcy, folic acid, or vitamin B12 levels in CSF in AD patients in comparison with controls, and the metaanalyses cannot provide definite results on this issue. Fourth, no studies regarding vitamin B6 in AD patients and controls were available to perform meta-analysis. Fifth, despite the comprehensive data included, due to the possible concurrent problems that trigger AD, the increased Hcy levels may not be directly associated with increased risk of AD.
CONCLUSION Our study provided comprehensive associations between AD and Hcy, folic acid, or vitamin B12 levels through meta-analyses. Data demonstrated that AD patients may have higher levels of Hcy, while lower levels of folic acid and vitamin B12 than healthy controls. High Hcy level and low folic acid level may correlate with increased risk of AD. The findings have potential implications for prevention and interventional treatment of AD. Future studies are needed to explore the causality between AD and Hcy, folic acid, or vitamin B12 levels and to examine the effects of folic acid and vitamin B supplementation in reducing risk of AD.
Limitations ACKNOWLEDGMENTS The major limitation of the present meta-analyses was the large between-study heterogeneity, which may arise from the gender, age, and ethnic differences of
This work was supported by the National Natural Science Foundation of China (Grant No. 31370745).
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Authors’ disclosures available online (http://j-alz. com/manuscript-disclosures/15-0140r1).
[15]
[16]
SUPPLEMENTARY MATERIAL The supplementary material is available in the electronic version of this article: http://dx.doi.org/10. 3233/JAD-150140.
[17]
[18]
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