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. 2015 Mar 3;9(5):1831–1840. doi: 10.3892/etm.2015.2327

Association of BDNF and BCHE with Alzheimer's disease: Meta-analysis based on 56 genetic case-control studies of 12,563 cases and 12,622 controls

HUIHUI JI 1,*, DONGJUN DAI 1,*, YUNLIANG WANG 2,*,✉, DANJIE JIANG 1,*, XINGYU ZHOU 1, PEIPEI LIN 1, XIAOSUI JI 1, JINFENG LI 2, YUZHENG ZHANG 2, HONGLEI YIN 2, RONGRONG CHEN 1, LINA ZHANG 1, MINGQING XU 3, SHIWEI DUAN 1, QINWEN WANG 1,✉
PMCID: PMC4471730  PMID: 26136901

Abstract

Alzheimer's disease (AD) is a common neurodegenerative disorder that can destroy the memory of sufferers and lead to distress for the individual and society. Brain-derived neurotrophic factor (BDNF) and butyrylcholinesterase (BCHE) are two genes associated with β-amyloid plaques and neurofibrillary tangles that are two key factors in the pathophysiology of AD. The aim of the current meta-analysis was to evaluate the association between BDNF Val66Met (rs6265), BDNF C270T (rs2030324) and BCHE-K (rs1803274) polymorphisms and AD. A comprehensive meta-analysis was performed using the online database PubMed without a time limitation. A total of 56 articles evaluating 12,563 cases and 12,622 controls were selected for the current meta-analysis. The results showed a moderate association of the BDNF C270T polymorphism with the risk of AD in Asians under a dominant model (P=0.03; odds ratio, 1.88; 95% confidence interval, 1.08–3.27). No other significant association was found during the meta-analysis for the other two polymorphisms (P>0.05). The current meta-analysis suggests that BDNF C270T is a risk factor for AD in Asians. This meta-analysis has been, to the best of our knowledge, the most comprehensive meta-analysis of BDNF Val66Met, BDNF C270T and BCHE-K to date.

Keywords: Alzheimer's disease, meta-analysis, BDNF Val66Met, BDNF C270T, BCHE-K, Asians

Introduction

Alzheimer's disease (AD) is a common neurodegenerative disorder that is the main cause of dementia. The clinical presentation of AD is characterized by progressive memory disorder and cognitive dysfunction (1). The worldwide prevalence of AD was 26.6 million in 2006, and this number is predicted to quadruple by 2050. The rapidly increased AD incidence is likely lead to a significant burden on family and society (2).

AD is a complex disease involving the interaction of genetic and environmental factors. It has been shown that AD development is contributed to by several elements, such as senile plaques, neurofibrillary tangles (NFTs), abnormally aggregated ‘reactive’ proteins like β-amyloid (Aβ) and tau, exposure to aluminum and brain inflammation (3). A genome-wide association study revealed that multiple mutations in candidate genes greatly increase the chance of developing AD (4). Genes such as brain-derived neurotrophic factor (BDNF) and butyrylcholinesterase (BCHE) are believed to play a significant role in AD progression (5–7).

BDNF is a member of the neurotrophic factor family and is encoded by a gene located on chromosome 11p13 (8). A previous study demonstrated that the levels of BDNF and its receptor, tyrosine receptor kinase B, were decreased in the frontal cortex and hippocampus of patients with AD (9). BDNF is known to protect against the neurotoxicity of the Aβ peptide and neural cell death by the aggregation of Aβ and tau proteins (10,11). Several single nucleotide polymorphisms (SNPs), such as Val66Met and C270T (rs2030324), in BDNF have been reported to be associated with AD (12–19).

BCHE is located on chromosome 3q26 (20), spanning over 73 kb with four exons and three large introns (21). The protein, BCHE, is an acetylcholine-hydrolyzing enzyme. BCHE is considered to be relevant to the progressive memory disorder and dementia in AD (22,23) and has been associated with NFTs and Aβ in the pathology of AD (24). In addition, BCHE has been found to play an important role in AD plaque maturation (25).

Inconsistent results have been reported in the previous studies on the association of BDNF and BCHE polymorphisms with AD. For BDNF Val66Met, there have been five positive results in Europeans (12–15) and Asians (16), and 21 negative results (among 18 studies) in Europeans (26–37), Asians (19,38–42) and Africans (29). For BDNF C270T, there have been four positive results in Europeans (13,17) and Asians (18,19) and 14 negative results in Europeans (28–31,34–37,43–45), Asians (40,41) and Africans (29). For BCHE-K variants, there have been six positive results in Europeans (46–51) and 22 negative results in Europeans (5,52–67) and Asians (68–72). Discrepancies among the previous association studies may have been the result of limited power, different ethnic backgrounds or the different processes and status in patients with AD. Meta-analysis can strengthen the power by combining data from different studies and can draw a more comprehensive conclusion by analyzing studies in different ethnicities (73–75). The aim of the current meta-analysis was to assess the association between the three polymorphisms and AD.

Materials and methods

Article retrieval

Articles were retrieved in January 2014 by searching PubMed without time or language restrictions. The following keywords were used: ‘Alzheimer disease BCHE association or Alzheimer disease BCHE polymorphism’ and ‘Alzheimer disease BDNF association or Alzheimer disease BDNF polymorphism’. The current meta-analysis included studies that met the following criteria: i) An original case-control study assessing the association of BDNF and BDHE with AD in humans; ii) a study containing sufficient information for the odds ratios (ORs) and 95% confidence intervals (CIs) to be obtained; iii) a study in which the genotype distribution of each polymorphism in controls met the Hardy-Weinberg equilibrium (HWE); iv) a study in the cumulative number of stages for one genetic locus was at least three. From each study, the following data were extracted or calculated: First author, publication year, country, ethnicity, number of cases and controls, HWE for controls, reported association results and the power of each study.

Data analysis

Arlequin software (76) was used to test whether the genotyping distribution in the controls was in HWE. The power of each study was calculated by a Power and Sample Size Calculation program (77). Cochran's Q statistic and I2 test (78) were used to evaluate the statistical heterogeneity. A fixed-effect model was used for the studies with minimal to moderate heterogeneity (I2<50%), and the random-effect model was used for the studies with significant heterogeneity (I2≥50%), with the exception of the allelic analysis. Subgroup analyses were performed in different inheritable models that contained dominant, recessive and additive models. Review Manager 5 (The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark) was used to estimate the combined ORs and CIs (79). Funnel plots were drawn to observe the potential publication bias. P<0.05 was considered to indicate a statistically significant difference.

Results

Article retrieval

As shown in Fig. 1, 104 articles were obtained from the two searches. Two non-human studies were excluded, as were five non-AD studies, three reviews, 35 studies that only focused on patients and nine case-control studies without genotyping information. In addition, six studies were included from the references. The genotypes in the controls of the case-control studies met the HWE. Finally, 56 articles (5,12–19,26–72) with 12,563 cases and 12,622 controls among 72 stages were involved in the present meta-analysis. The characteristics of the included studies are shown in Table I.

Figure 1.

Figure 1.

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Flowchart of the selection process in the meta-analysis. AD, Alzheimer's disease; BCHE, butyrylcholinesterase; BDNF, brain-derived neurotrophic factor.

Table I.

Characteristics of the case-control studies in the current meta-analysis.

First author (ref) Year Country Ethnicity Cases/controls (n/n) HWE Result Power
BDNF Val66Met
  Ventriglia (12) 2002 Italy Europeans 130/111 Yes S 0.052
  Saarela (13) 2006 Finland Europeans 97/101 Yes S 0.086
  Nacmias (26) 2004 Italy Europeans 83/97 Yes NS 0.117
  Combarros (27) 2004 Spain Europeans 237/218 Yes NS 0.197
  Tsai (38) 2004 China Asians 163/89 Yes NS 0.164
  Bian (39) 2005 China Asians 203/239 Yes NS 0.266
  Lee (28) 2005 USA Europeans 95/70 Yes NS 0.119
  Nishimura (19) 2005 Japan Asians 172/275 Yes NS 0.262
  Desai 1 (29) 2005 USAa Europeans 995/671 Yes NS 0.516
  Desai 2 (29) 2005 USAb Africans 64/45 Yes NS 0.054
  Matsushita (16) 2005 Japan Asians 487/471 Yes S 0.512
  Vepsäläinen (30) 2005 Finland Europeans 375/460 NA NS 0.254
  Bodner (31) 2005 USA Europeans 256/194 Yes NS 0.192
  Li 1 (32) 2005 UK Europeans 359/396 Yes NS 0.285
  Li 2 (32) 2005 USAc Europeans 188/361 Yes NS 0.222
  Li 3 (32) 2005 USAd Europeans 388/349 Yes NS 0.271
  Forero (33) 2006 Colombia Europeans 101/168 Yes NS 0.111
  Akatsu (40) 2006 Japan Asians 95/108 Yes NS 0.146
  Zhang (34) 2006 USA Europeans 295/250 Yes NS 0.224
  Tsai (41) 2006 China Asians 175/189 Yes NS 0.229
  Huang (35) 2007 USA Europeans 220/128 Yes NS 0.124
  He (42) 2007 China Asians 513/575 Yes NS 0.564
  Cozza (37) 2008 Italy Europeans 251/97 Yes NS 0.139
  Feher (14) 2009 Hungary Europeans 160/164 Yes S 0.211
  Pivac (15) 2011 Croatia Europeans 211/402 Yes S 0.235
  Boiocchi (36) 2013 Italy Europeans 191/408 Yes NS 0.262
BDNF C270T
  Kunugi (18) 2001 Japan Asians 170/498 Yes S 0.084
  Riemenschneider (43) 2002 Germany Europeans 210/188 Yes NS 0.076
  Nishimura (44) 2004 Brazil Europeans 188/188 Yes NS 0.088
  Olin (17) 2005 US Europeans 212/202 Yes S 0.076
  Lee (28) 2005 USA Europeans 106/73 Yes NS 0.063
  Nishimura (19) 2005 Japan Asians 172/275 Yes S 0.073
  Desai 1 (29) 2005 USAa Europeans 719/523 Yes NS 0.207
  Desai 2 (29) 2005 USAb Africans 58/42 Yes NS 0.056
  Vepsäläinen (30) 2005 Finland Europeans 375/460 Yes NS 0.457
  Bodner (31) 2005 USA Europeans 256/194 Yes NS 0.088
  Akatsu (40) 2006 Japan Asians 95/108 Yes NS 0.065
  Zhang (34) 2006 USA Europeans 295/250 Yes NS 0.113
  Saarela (13) 2006 Finland Europeans 97/101 Yes S 0.089
  Tsai (41) 2006 China Asians 175/189 Yes NS 0.096
  Huang (35) 2007 USA Europeans 220/128 Yes NS 0.081
  Cozza (37) 2008 Italy Europeans 251/97 Yes NS 0.091
  Cousin (45) 2011 France Europeans 425/470 Yes NS 0.152
  Boiocchi (36) 2013 Italy Europeans 192/384 Yes NS 0.308
BCHE-K
  Lehmann (51) 1997 UK Europeans 74/104 NA S 0.083
  Singleton (63) 1998 UK Europeans 119/83 Yes NS 0.111
  Crawford (62) 1998 USA Europeans 391/201 Yes NS 0.182
  Brindle (64) 1998 USA Europeans 188/165 NA NS 0.161
  Piccardi (55) 2007 Italy Europeans 158/118 Yes NS 0.109
  Kehoe (60) 1998 UK Europeans 181/71 Yes NS 0.093
  Ki (71) 1999 Korea Asians 78/74 NA NS 0.231
  Wiebusch (50) 1999 Canada Europeans 135/70 Yes S 0.094
  Grubber (59) 1999 USA Europeans 245/241 NA NS 0.137
  Tilley (58) 1999 UK Europeans 177/118 Yes NS 0.145
  McIlroy (49) 2000 Ireland Europeans 175/187 Yes S 0.175
  Yamamoto (70) 1999 Japan Asians 203/288 NA NS 0.087
  Lee (69) 2000 China Asians 89/101 NA NS 0.086
  Mattila (57) 2000 Finland Europeans 80/67 Yes NS 0.077
  Bi 2001 China Asians 38/40 Yes NS 0.171
  Prince (56) 2001 Sweden Europeans 201/166 Yes NS 0.103
  Raygani (47) 2004 Iran Europeans 105/129 Yes S 0.146
  Combarros (46) 2005 Spain Europeans 187/172 Yes S 0.134
  Deniz-Naranjo (54) 2007 Spain Europeans 282/312 Yes NS 0.248
  Mateo (53) 2008 Spain Europeans 231/221 Yes NS 0.144
  Scacchi (5) 2009 Italy Europeans 471/254 Yes NS 0.279
  Simão-Silva 2013 Brazil Europeans 78/80 Yes NS 0.108
  Russ (65) 1998 UK Europeans 203/122 NA NS 0.100
  Hiltunen (61) 1998 Finland Europeans 59/59 Yes NS 0.090
  Yamada (72) 1998 Japan Asians 48/107 Yes NS 0.096
  Alvarez-Arcaya (48) 2000 Spain Europeans 202/249 NA S 0.141
  Helbecque (66) 1998 Variouse Europeans 336/344 Yes NS 0.272
  Laws (67) 1999 Australia Europeans 237/348 NA NS 0.239
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a

Caucasian descent

b

African-American.

c

Samples collected from the University of California, San Diego, CA, USA

d

samples collected from Washington University Alzheimer's Disease Research Center patient registry (Seattle, WA, USA).

e

France, UK, Spain, Italy and the Netherlands. HWE, Hardy-Weinberg equilibrium; NS, not significant; S, significant; NA, not applicable; BDNF, brain-derived neurotrophic factor; BCHE, butyrylcholinesterase.

BDNF Val66Met

A total of 23 articles with 26 stages involving 6,504 patients with AD and 6,636 controls were included for the meta-analysis of BDNF Val66Met. Significant statistical heterogeneity was found at the allelic level (I2=58%), under the dominant model (I2=56%) and the additive model (I2=53%). The major allele frequency of BDNF Val66Met was 0.805 in Europeans [International Haplotype Mapping Project panel derived from Utah residents with Northern and Western European ancestry (HapMap-CEU)], higher than the frequency in Asians [HapMap-Han Chinese in Beijing, China (HCB), 0.733; HapMap-Japanese in Tokyo Japan (JPT), 0.682] and Africans [HapMap-Yoruba in Ibadan, Nigeria (YRI), 0.004]. The ethnic differences for BDNF Val66Met were low between different populations [Fixation index (Fst)=0.1006]; therefore, the meta-analysis was also performed by ethnicity. No significant association was found in the meta-analysis on allelic analysis (P=0.99; OR, 1.00; 95% CI, 0.91–1.10; Table II) or under the other models for combined and stratified populations (P>0.05, Table II).

Table II.

Meta-analysis of the association of the BDNF Val66Met, BDNF C270T and BCHE-K polymorphisms with Alzheimer's disease.

A, BDNF Val66Met polymorphism
Genetic model Cases/controls (n/n) Ethnicity No. of studies OR (95% CI) P-value I2 (%) Power
Overall (M vs. V) 6504/6636 Overall 26 1.00 (0.91–1.10) 0.99 58 1.000
4632/4645 Europeans 18 1.01 (0.88–1.15) 0.89 65 0.999
1808/1946 Asians 7 0.95 (0.87–1.04) 0.26 38 0.976
64/45 Africans 1 1.18 (0.27–5.06) 0.82 NA 0.054
Dominant (MM/MV vs. VV) 6129/5982 Overall 25 1.03 (0.90–1.18) 0.65 56 1.000
4257/4185 Europeans 17 1.03 (0.87–1.22) 0.72 64 1.000
1808/1946 Asians 7 0.98 (0.85–1.13) 0.82 16 0.938
64/45 Africans 1 1.19 (0.27–5.24) 0.82 NA 0.060
Recessive (MM vs. MV/VV) 6129/6176 Overall 25 0.90 (0.80–1.02) 0.43 42 0.997
4257/4185 Europeans 17 0.95 (0.78–1.15) 0.58 44 0.880
1808/1946 Asians 7 0.87 (0.74–1.02) 0.09 44 0.918
64/45 Africans 1 NA NA NA NA
Additive (MM vs. VV) 3650/3753 Overall 25 0.92 (0.71–1.18) 0.50 53 0.988
2160/2419 Europeans 17 0.82 (0.57–1.18) 0.28 59 0.934
1393/1271 Asians 7 1.11 (0.85–1.45) 0.43 9 0.631
97/63 Africans 1 0.85 (0.33–2.15) 0.73 NA 0.085
B, BDNF C270T polymorphism
Genetic model Cases/controls (n/n) Ethnicity No. of studies OR (95% CI) P-value I2 (%) Power
Overall (T vs. C) 4216/4370 Overall 18 1.12 (0.91–1.37) 0.30 63 0.986
3546/3258 Europeans 13 1.01 (0.83–1.24) 0.92 58 0.982
612/1070 Asians 4 1.80 (0.99–3.27) 0.06 62 0.154
58/42 Africans 1 0.71 (0.17–2.94) 0.64 NA 0.056
Dominant (TT/TC vs. CC) 4216/4370 Overall 18 1.10 (0.87–1.39) 0.40 62 0.999
3546/3258 Europeans 13 0.99 (0.78–1.25) 0.91 58 0.998
612/1070 Asians 4 1.88 (1.08–3.27) 0.03a,b 53 0.241
58/42 Africans 1 0.70 (0.17–2.99) 0.63 NA 0.064
Recessive (TT vs. TC/CC) 4216/4370 Overall 18 1.12 (0.88–1.42) 0.37 0 0.725
3546/3258 Europeans 13 1.12 (0.88–1.43) 0.37 0 0.737
612/1070 Asians 4 1.33 (0.03–51.71) 0.88 64 0.062
58/42 Africans 1 NA NA NA NA
Additive (TT vs. CC) 3528/3609 Overall 18 1.17 (0.88–1.54) 0.29 0 0.722
2929/2560 Europeans 13 1.17 (0.88–1.55) 0.29 0 0.738
545/1011 Asians 4 1.40 (0.03–57.09) 0.86 64 0.063
54/38 Africans 1 NA NA NA NA
C, BCHE-K polymorphism
Genetic model Cases/controls (n/n) Ethnicity No. of studies OR (95% CI) P-value I2 (%) Power
Overall (K vs. W) 4769/4242 Overall 27 1.07 (0.94–1.21) 0.31 56 1.000
4313/3632 Europeans 22 1.06 (0.92–1.22) 0.45 63 0.994
456/610 Asians 5 1.17 (0.92–1.47) 0.20 0 0.341
Dominant (KK/KW vs. WW) 3659/2992 Overall 20 1.01 (0.84–1.22) 0.89 65 0.999
3573/2845 Europeans 18 1.02 (0.83–1.24) 0.88 69 0.998
86/147 Asians 2 0.97 (0.55–1.73) 0.93 0 0.151
Recessive (KK vs. KW/WW) 3452/2628 Overall 19 1.15 (0.85–1.54) 0.36 0 0.455
3366/2481 Europeans 17 1.19 (0.88–1.61) 0.25 0 0.433
86/147 Asians 2 0.35 (0.05–2.22) 0.26 0 0.073
Additive (KK vs. WW) 2430/1995 Overall 19 1.19 (0.90–1.58) 0.23 0 0.439
2372/1891 Europeans 17 1.23 (0.92–1.65) 0.15 0 0.418
58/104 Asians 2 0.36 (0.06–2.29) 0.28 0 0.073
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a

P≤0.05

b

significance of P-value lost following correction by multiple testing. BDNF, brain-derived neurotrophic factor; BCHE, butyrylcholinesterase; NA, not applicable; OR, odds ratio; CI, confidence interval.

BDNF C270T

A total of 17 articles with 18 stages involving 4,216 patients with AD and 4,370 controls were included for the meta-analysis of the BDNF C270T polymorphism. Significant heterogeneity was observed in the meta-analysis at the allelic level (I2=63%) and under the dominant model (I2=62%). The frequency of the BDNF C270T allele was 0.667 in Chinese subjects (HapMap-HCB), higher than that in the Japanese group (HapMap-JPT, 0.455), Europeans (HapMap-CEU, 0.570) and Africans (HapMap-YRI, 0.550). Further analysis showed a low ethnic difference for BDNF C270T (Fst=0.0230). No significant association between BDNF C270T and AD was observed at the allelic level (P=0.30; OR, 1.12; 95% CI, 0.91–1.37; Table II). A further subgroup meta-analysis by ethnicity showed a significant association between BDNF C270T and AD in Asians under a dominant model (P=0.03; OR, 1.88; 95% CI, 1.08–3.27; Table II and Fig. 2).

Figure 2.

Figure 2.

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Forest plot of the association of the brain-derived neurotrophic factor C270T polymorphism with Alzheimer's disease in Asians. M-H, Mantel-Haenszel; CI, confidence interval.

BCHE-K

A total of 28 articles with 4,894 patients with AD and 4,367 controls were included for the meta-analysis of the BCHE-K variant. Although minimal ethnic differences were found in Europeans and Asians (Fst=0.0009), significant heterogeneity was found in the meta-analysis on the allelic level (I2=56%) and under the dominant model (I2=65%); however, no significant association was found at the allelic level (P=0.31; OR, 1.07; 95% CI, 0.94–1.21; Table II). Subgroup meta-analysis also did not yield any significant results (P>0.05, Table II).

Power analyses

The power analyses in this meta-analysis were calculated under a moderate risk of AD (OR, 1.2; Tables I and II). The power was 1.000 for BDNF Val66Met, 0.986 for BDNF C270T and 1.000 for the BCHE-K variant (Table II), which was considerably higher than that in each of the individual studies (Table I). No publication bias was found in the meta-analyses of the three SNPs (Fig. 3).

Figure 3.
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Funnel plots of the association of the (A) BDNF Val66Met, (B) BDNF C270T and (C) BCHE-K polymorphisms with Alzheimer's disease. BDNF, brain-derived neurotrophic factor; BCHE, butyrylcholinesterase; SE, standard error; OR, odds ratio.

Discussion

In the present study, 56 studies (72 stages) among 12,563 cases and 12,622 controls were analyzed to assess the association of the BDNF Val66Met, BDNF C270T and BCHE-K variants with AD. The results showed a moderate association between BDNF C270T and AD in Asians (P=0.03; OR, 1.88; 95% CI, 1.08–3.27; Table II and Fig. 2) but no significant associations were observed in the other meta-analyses.

The BDNF Val66Met polymorphism has been shown to impair the secretion of BDNF (80), and to be able to change brain morphology and cognitive function (81). Previous studies have reported five positive results (12–16) and 21 negative results (19,26–42) between the BDNF Val66Met polymorphism and AD. In the present meta-analysis, no significant association was found between BDNF Val66Met and AD (P>0.05, Table II). This was consistent with a former meta-analysis (82). The current meta-analysis of BDNF Val66Met included 23 articles, seven more than the previous study. In addition, meta-analyses were performed under various genetic models, including dominant, recessive and additive models. Subgroup meta-analysis by ethnicity was also conducted, although no statistically significant results were obtained.

The BDNF C270T polymorphism is located in a non-coding region and may affect the BDNF expression in the neural soma, dendrites or axonal regions (83). Heterozygous carriers of the T-allele tend to have a higher risk of developing AD than non-carriers (36). There have been a total of four significant results (13,17–19) and 14 non-significant results (28–31,34–37,40,41,43–45) among the previous association studies between the BDNF C270T polymorphism and AD. In the present meta-analysis, the BDNF C270T polymorphism was found to increase the risk of AD by 88% in Asians under the dominant model. No significant association was found in the other analyses (P>0.05, Table II). A strong power was shown in the meta-analysis of BDNF C270T polymorphism (0.986). Compared with a former meta-analysis that showed no positive results (82), the current meta-analysis of BDNF C270T included 18 studies, more than the 12 in the previous study (82); the meta-analyses were performed under various genetic models, and subgroup meta-analyses by ethnicity were also conducted. With a larger sample size and more comprehensive analysis, the present study showed a more reliable conclusion than the previous study.

The K variant alone does not decrease BCHE activity, but acts in synergy with APOE4 polymorphism to increase the risk of AD (84). Additionally, the BCHE-K variant promotes fibril formation by participating in the transformation of Aβ from an initially benign form to an eventually malignant form. The BCHE-K variant acts as a general candidate risk factor of AD (84,85). Six significant results (46–51) and 22 non-significant results (5,52–72) were found in previous studies on the association between the BCHE-K variant and AD. The power of BCHE-K was 1.000, which was sufficiently strong for a precise conclusion to be drawn. The current study showed no significant association between the BCHE-K variant and AD; this was consistent with a previous meta-analysis (86). The present study involved 27 stages, six more than the former study. The studies involved in the present meta-analysis met the HWE and were performed under various genetic models with subgroup meta-analysis by ethnicity. With stricter inclusion criteria, a stronger power and more comprehensive analysis, the present meta-analysis of BCHE-K was an improvement on the former one.

There were certain limitations in the meta-analysis. Firstly, publication bias may exist, as the negative-result studies are less likely to be published and may be missed, which may influence the results. Secondly, the majority of studies investigating the association between the three polymorphisms and AD were carried out in the European and Asian populations. The number of studies in other populations, such as Africans, was limited. Future studies in other ethnic populations are warranted. Thirdly, AD is a complex disease. Different statuses in AD may affect the results of the study; however, no detailed information of the AD diagnostic criteria was available from previous studies. Future case-control studies with more comprehensive information are required. Fourthly, there are 5,724 polymorphisms in BDNF and 5,059 polymorphisms in BCHE. The current study only focused on two polymorphisms of BDNF and one polymorphism of BCHE, which may not fully show the function of those two genes. Studies investigating a wider range of polymorphisms are required to improve the representation of the two genes. Fifthly, APOE is a known pivotal gene in the AD pathogenesis but no APOE genotype was included in any of the studies. Thus, any hidden interaction of the APOE genotype with the tested three polymorphisms may have been missed in the current meta-analysis. Sixthly, although a moderate association of the BDNF C270T polymorphism with the risk of AD was observed in Asians under a dominant model (P=0.03; OR, 1.88; 95% CI, 1.08–3.27), the significance was not retained following correction by multiple testing. This result should therefore be taken with caution. Finally, there was high heterogeneity in the BDNF C270T variant under the dominant model in Asians (P=0.03, I2=53%, Table II). We speculated that the number of participants was the source of the heterogeneity, as the studies with limited samples tended to produce negative results (n<200, P>0.05) in contrast to significant results produced in the studies with sufficient samples (n>200, P<0.05).

In conclusion, the present comprehensive meta-analysis suggested a moderate association between the BDNF C270T polymorphism and AD in Asians under the dominant model. Further studies focusing on a wider range of ethnic populations are required to confirm the results of the study.

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Acknowledgements

The study was supported by grants from the National Natural Science Foundation of China (nos. 31100919 and 81371469), the 973 program from the Ministry of Science and Technology of China (no. 2013CB835100), the Natural Science Foundation of Zhejiang Province (no. LR13H020003), the Disciplinary Project of Ningbo University (no. B01350104900), the KC Wong Magna Fund in Ningbo University, the Program for Professor of Special Appointment (Eastern Scholars) at Shanghai Institutions of Higher Learning and the Key Basic Research Foundation of Science and Technology Commission of Shanghai Municipality (no. 13JC1403700).

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