Abstract
Background
Alzheimer's disease is complex, with variants in multiple genes contributing to interactions increasing risk for the disease. Brain‐derived neurotrophic factor (BDNF) promotes neuronal survival and modulates hippocampal‐dependent memory.
Methods
We examined 11 SNPs that spanned the gene on chromosome 11p14 in 220 Alzheimer's patients and 128 control spouses.
Results
Not all of the SNPs were informative, due to minor allele frequencies of <2%. Neither C270T nor two SNPs that reside proximal to exon V had significant association with the disease. However, we did find that the heterozygous form of the rs6265 SNP (Val66Met), as well as the diplotype of three SNPs (rs6265, rs11030104, rs2049045; H1‐GTC/H2‐ACG) all were highly significant in APOE 4 non‐carriers (OR = 2.734; p = 0.0096).
Conclusion
The combination of the diplotypes for three SNPs exhibited significant p values for Alzheimer's APOE 4 non‐carriers. The two SNPs (rs11030104 and rs2049045) are found between exons VI and VII, while the Val66Met polymorphism is located in the coding exon VIII; the total distance for the three SNPs is 14308 bp. Whether the SNPs are involved with alternative splicing of the VII/VIII transcript is of considerable interest.
Keywords: Alzheimer's disease, brain‐derived neurotrophic factor
Alzheimer's disease is an age‐related progressive neurodegenerative disorder characterised by severe cognitive impairment. The E4 allele of apolipoprotein E (APOE) is the most prevalent identified risk factor and accounts for 40–50% of the risk as a single factor. The disease is complex with numerous systems, cells and molecules affected. Several genes may interact to cause the disease or serve as risk factors. Measurement of any one component may be small and variable, depending upon the presence of other factors. Brain‐derived neurotrophic factor (BDNF) promotes neuronal survival and is known to be reduced in affected cortical regions in Alzheimer's disease.1,2 Several polymorphisms in the gene have been identified that are associated with Alzheimer's disease, but the reports are conflicting (www.alzgene.org).
Key points
Alzheimer's disease is complex; multiple genes may interact, increasing risk for the disease.
Brain‐derived neurotrophic factor promotes neuronal survival and modulates hippocampal‐dependent memory.
The combination of diplotypes for three SNPs increased risk for Alzheimer's disease in APOE 4 non‐carriers.
The gene for BDNF, located on chromosome 11p14, consists of eight exons, with the coding region in the last exon. There are two transcripts, due to alternative splicing. There are seven non‐coding exons for one expressed transcript and 11 non‐coding exons for the second transcript which may be non‐protein coding.3 The type I transcript uses a single splice acceptor site in the main protein coding exon VIII. One of seven transcript classes may be formed when transcription is initiated at either exon I, II, … VII with the donor site spliced to the major coding exon VIII acceptor site. Four predicted translation products have been identified thus far.3
The two most common polymorphisms studied in Alzheimer's disease are the most terminal polymorphism (rs6265) with a G/A (Val/Met) at codon 66 in the coding exon VIII and the C270T polymorphism (corrected to C132T)4 which is untranslated in exon 5, contributing to an mRNA transcript class. The Val66Met polymorphism was associated with Alzheimer's disease in an Italian population5 but not in other studies.6,7,8,9,10,11,12,13,14,15 Likewise, the C270T polymorphism was associated with the disease in Japanese and European patients13,14,16,17 but not in other groups.10,12
To verify a potential role for BDNF polymorphisms in Alzheimer's disease, we analysed 11 SNPs (five tagSNPs and five non‐synonymous SNPs including the Val66Met, as well as the C270T polymorphism) that spanned the gene. We also analysed the data according to APOE status.
Table 1 SNP positions and variation.
| dbSNP ID | Chromosome position* | AF411339 position† | Alleles | Tagging SNPs in HapMap Project |
|---|---|---|---|---|
| rs11030121 | 26523448 | 39149 | G‐A | Yes |
| rs2049046 | 26511016 | 51579 | A‐T | Yes |
| C270T | 26508860 | 53620 | C‐T | |
| rs2049045 | 26481482 | 81114 | C‐G | Yes |
| rs11030104 | 26471758 | 90836 | T‐C | Yes |
| rs8192466‡ | 26467348 | 95231 | C‐T (Thr2Ile) | |
| rs6265 | 26467157 | 95422 | A‐G (Val66Met) | |
| rs1048218‡ | 26467128 | 95451 | G‐T (Gln75His) | |
| rs1048220‡ | 26466979 | 95600 | G‐T (Arg125Met) | |
| rs1048221‡ | 26466973 | 95606 | G‐T (Arg127Leu) | |
| rs7124442 | 26464282 | 98296 | G‐A | Yes |
*Chromosome position from the NCBI SNP database; †GenBank AF411339 position; ‡minor allele frequencies of <2% in our samples.
Methods
Subjects
The patients and family members were recruited from communities in Texas and Georgia, as well as from the Memory Disorders Clinic at the Medical College of Georgia. Medical records were obtained on each patient and the clinical diagnosis of probable Alzheimer's disease was made according to NINCDS‐ADRDA criteria.18 This included a documented progressive decline in cognitive function and appropriate blood work to rule out other medical conditions, including thyroid and vitamin B12 deficiencies. In addition, we included in the diagnosis, results from a CT or MRI scan of the brain which indicated the presence of cortical atrophy but no evidence of strokes or tumours. The patients were Caucasian and of European descent. Spouses of patients and of siblings of similar age, ethnic background and similar environmental exposure served as controls. All participants or the authorised representatives of the patients gave consent for the study, in accordance with the Institutional Review Board guidelines. We also included 36 patients with the diagnosis of Alzheimer's disease from the National Cell Repository. The groups were analysed separately for population stratification with Structure 2.1 software (http://pritch.bsd.uchicago.edu/software.html) and no significant differences were found.19
There were 220 patients (155 females and 65 males) with an average age of onset of 71.0±8.0 years (range 50–92 years; 175 with age of onset >64 years) and 128 control spouses (75 females and 53 males) with an average age at enrolment of 72.0±8.0 years (range 50–88 years).
Genotyping
SNP selection
Using the 10/04 HapMap Project (www.hapmap.org), there were 15 SNPs that spanned 59 kb across the BDNF gene, from exon III to exon VIII, the coding exon. All 15 of the SNPs were in tight linkage disequilibrium and were in one haplotype block.20 Eleven SNPs were selected that spanned the gene from intron 3 to exon VIII: five tagSNPs, five non‐synonymous SNPs and the C127T polymorphism. The SNPs are listed in table 1 and were genotyped using fluorescent‐detected single base extension21 with the SNaPshot Multiplex kit (Applied Biosystems, Foster City, CA) as described.22 APOE and the BDNF polymorphisms (Val66Met and C270T) were genotyped as described previously.5,17,23
Statistical analysis
Hardy‐Weinberg equilibrium tests were performed separately among patient and control groups for each SNP, using Arlequin24; no significant deviations were observed. Power analysis was performed for the 225 patients and 127 controls, using G*Power and the power was 0.9978.25 When the samples were divided into APOE 4 carriers and non‐carriers, the power was 0.8109 for the carriers and 0.9354 for the non‐carriers. Logistic regression was performed using SAS 9.1 to investigate the association between the SNPs and Alzheimer's disease. Pairwise linkage disequilibrium for the SNPs was evaluated with Arlequin. Haplotypes were inferred for each individual using PHASE.26 The haplotype data for the individuals with EM probabilities greater than 85% were exported to SAS for logistic regression analysis to determine the risk associated with particular haplotypes.
Results
Of the 11 BDNF SNPs that were analysed (table 1), four had minor allele frequencies lower than 2% in our samples and even though they were in the coding region, they were excluded from further analysis (rs1048221, rs1048220, rs1048218 and rs8192466). Comparisons of the allele frequencies or the genotype frequencies between patients and controls did not reveal significant differences, although the p values for the heterozygous genotypes for the patients with the three adjacent SNPs (rs6265, rs11030104 and rs2049045) approached significance (p = 0.096, 0.075 and 0.056, respectively) (table 2). When the patients and controls were divided according to APOE 4 status, the genotype frequencies of two of the three SNPs were significantly different between APOE 4 non‐carrier patients and controls (table 3). Comparisons of the genotype frequencies between patients and controls in APOE 4 non‐carriers for SNPs rs6265 (Val66Met) and rs2049045 gave p values of 0.0327 and 0.0226, respectively, while that for SNP rs11030104 was 0.0534. The p values for APOE 4 carriers and for the remaining four SNPs in either group were not significant.
Table 2 Allele and genotype frequencies*.
| SNP ID | Genotypic comparison | Allelic comparison | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Alzheimer's disease | Control | p Value† | Alzheimer's disease | Control | p Value | ||||
| n (%) | n (%) | n (%) | n (%) | ||||||
| rs7124442 | AA | 95 (43.18) | 55 (43.31) | A | 287 (65.23) | 163 (64.17) | 0.8779 | ||
| GA | 97 (44.09) | 53 (41.73) | 0.9884 | G | 163 (34.77) | 91 (35.83) | |||
| GG | 28 (12.73) | 19 (14.96) | |||||||
| rs6265 | AA | 4 (1.82) | 5 (3.91) | A | 74 (16.82) | 35 (13.67) | 0.1909 | ||
| AG | 66 (30.00) | 25 (19.53) | 0.0956 | G | 366 (83.18) | 221 (86.33) | |||
| GG | 150 (68.18) | 98 (76.56) | |||||||
| rs11030104 | CC | 5 (2.27) | 5 (3.91) | C | 83 (18.86) | 38 (14.84) | 0.1338 | ||
| CT | 73 (33.18) | 28 (21.88) | 0.0749 | T | 357 (81.14) | 218 (85.16) | |||
| TT | 142 (64.55) | 95 (74.21) | |||||||
| rs2049045 | CC | 153 (69.54) | 100 (78.12) | C | 369 (83.86) | 223 (87.11) | 0.1304 | ||
| CG | 63 (28.64) | 23 (17.97) | 0.0561 | G | 71 (16.14) | 33 (12.89) | |||
| GG | 4 (1.82) | 5 (3.91) | |||||||
| C270T | CC | 202 (91.82) | 113 (88.28) | C | 420 (95.45) | 241 (94.14) | 0.7298 | ||
| CT | 16 (7.27) | 15 (11.72) | 0.6545 | T | 20 (4.55) | 15 (5.86) | |||
| TT | 2 (0.91) | 0 | |||||||
| rs2049046 | AA | 61 (27.73) | 36 (28.13) | A | 239 (54.32) | 133 (51.95) | 0.2969 | ||
| AT | 117 (53.18) | 61 (47.65) | 0.3662 | T | 201 (45.68) | 123 (48.05) | |||
| TT | 42 (19.09) | 31 (24.22) | |||||||
| rs11030121 | AA | 22 (10.00) | 13 (10.16) | A | 143 (32.50) | 83 (32.42) | 0.7252 | ||
| GA | 99 (45.00) | 57 (44.53) | 0.9142 | G | 297 (67.50) | 173 (67.58) | |||
| GG | 99 (45.00) | 58 (45.31) | |||||||
*The SNPs with minor allele frequency of <2% are not listed here; †overall genotypic p value by logistic regression, adjusted for age, gender and APOE 4 status.
Table 3 APOE 4 status for risk SNPs.
| SNP ID | APOE 4 carriers | APOE 4 non‐carriers | |||||
|---|---|---|---|---|---|---|---|
| Alzheimer's disease | Control | p Value | Alzheimer's disease | Control | p Value | ||
| rs6265 | AA | 3 (1.99) | 0 | 1 (1.45) | 5 (5.15) | ||
| AG | 43 (28.48) | 8 (25.81) | 0.9324 | 23 (33.33) | 17 (17.53) | 0.0327* | |
| GG | 105 (69.53) | 23 (74.19) | 45 (65.22) | 75 (77.32) | |||
| A | 49 (16.23) | 8 (12.90) | 0.5118 | 25 (18.12) | 27 (13.92) | 0.2766 | |
| G | 253 (83.77) | 54 (87.10) | 113 (81.88) | 167 (86.08) | |||
| rs11030104 | CC | 4 (2.65) | 0 | 1 (1.45) | 5 (5.15) | ||
| CT | 48 (31.79) | 8 (25.81) | 0.7416 | 25 (36.23) | 20 (20.62) | 0.0534* | |
| TT | 99 (65.56) | 23 (74.19) | 43 (62.32) | 72 (74.23) | |||
| C | 56 (18.54) | 8 (12.90) | 0.337 | 27 (19.57) | 30 (15.46) | 0.3457 | |
| T | 246 (81.46) | 54 (87.10) | 111 (80.43) | 164 (85.54) | |||
| rs2049045 | CC | 108 (71.52 | 24 (77.42) | 45 (65.22) | 76 (78.36) | ||
| CG | 40 (26.49) | 7 (22.58) | 0.8726 | 23 (33.33) | 16 (16.49) | 0.0226* | |
| GG | 3 (1.99) | 0 | 1 (1.45) | 5 (5.15) | |||
| C | 256 (84.77) | 55 (88.71) | 0.4243 | 113 (81.88) | 168 (86.60) | 0.0525 | |
| G | 46 (15.23) | 7 (11.29) | 25 (18.12) | 26 (13.40) | |||
Results: n (%)
*p<0.05
To further investigate the possible association of the three SNPs (rs6265, rs11030104 and rs2049045) with the disease, we examined their genotype combinations. The heterozygous combination of AG/CT/CG had a significantly higher frequency among the patients when compared with the controls (28.64% v 17.97%). When compared with the homozygous genotype, GG/TT/CC, there was an increased risk for the disease (p = 0.0283, OR = 2.01) (table 4). The p value was even more significant in APOE 4 non‐carriers (33.33% v 16.49%) when heterozygous genotype combinations were compared with homozygous genotypes (p = 0.0160, OR = 2.57).
Table 4 Combined genotypes of the risk SNPs: rs6265/rs11030104/rs2049045.
| All subjects | APOE 4 carriers | APOE 4 non‐carriers | ||||
|---|---|---|---|---|---|---|
| Alzheimer's disease | Control | Alzheimer's disease | Control | Alzheimer's disease | Control | |
| AA/CC/GG | 4 (1.82) | 5 (3.91) | 3 (1.99) | 0 | 1 (1.45) | 5 (5.15) |
| AG/CT/CC | 3 (1.36) | 1 (0.78) | 3 (1.99) | 0 | 0 | 1 (1.03) |
| AG/CT/CG | 63 (28.64) | 23 (17.97) | 40 (26.49) | 7 (22.58) | 23 (33.33) | 16 (16.49) |
| AG/TT/CC | 0 | 1 (0.78) | 0 | 1 (3.23) | 0 | 0 |
| GG/CC/CC | 1 (0.45) | 0 | 1 (0.66) | 0 | 0 | 0 |
| GG/CT/CC | 7 (3.18) | 4 (3.13) | 5 (3.31) | 1 (3.23) | 2 (2.90) | 3 (3.09) |
| GG/TT/CC | 142 (64.55) | 94 (73.43) | 99 (65.56) | 22 (70.96) | 43 (62.32) | 72 (74.24) |
| AG/CT/CG v | p = 0.0238* | p = 0.5934 | p = 0.0160* | |||
| GG/TT/CC | OR = 2.01 | OR = 1.29 | OR = 2.57 | |||
| 95% CI: 1.10 to 3.67 | 95% CI: 0.51 to 3.28 | 95% CI: 1.193 to 5.55 | ||||
Results: n (%)
*p<0.05
Haplotypes
The seven SNPs described in table 2 are in linkage disequilibrium and reside in one haplotype block. Within that block, four haplotypes had frequencies higher than 5% (data not shown). Each haplotype was compared with the combination of the others. As the allelic associations were not significant, the haplotypes were also not significant. However, when the diplotypes for the three SNPs (rs6265, rs11030104 and rs2049045) were compared, the diplotype H1 (GTC)/H2 (ACG) had an odds ratio of 2.734 (p = 0.0096) when compared with all others in APOE 4 non‐carriers (table 5). Even with Bonferroni correction of five multiple tests, the p value remains significant at p = 0.048.
Table 5 SNP haplotypes and diplotypes: rs6265/rs11030104/rs2049045.
| All subjects | APOE 4 carriers | APOE 4 non‐carriers | ||||
|---|---|---|---|---|---|---|
| Alzheimer's disease | Control | Alzheimer's disease | Control | Alzheimer's disease | Control | |
| Haplotype | ||||||
| H1 | 357 (81.2) | 217 (84.8) | 246 (81.5) | 53 (85.5) | 111 (80.4) | 164 (84.5) |
| H2 | 71 (16.1) | 33 (12.9) | 46 (15.2) | 7 (11.3) | 25 (18.1) | 26 (13.4) |
| Other | 12 (2.7) | 6 (2.3) | 10 (3.3) | 2 (3.2) | 2 (1.5) | 4 (2.1) |
| Total | 440 | 256 | 302 | 62 | 138 | 194 |
| H1 v others | p = 0.1941 | p = 0.4350 | p = 0.3457 | |||
| OR = 0.737 | OR = 0.737 | OR = 0.754 | ||||
| 95% CI: 0.465 to 1.168 | 95% CI: 0.342 to 1.586 | 95% CI: 0.419 to 1.356 | ||||
| H2 v others | p = 0.1304 | p = 0.4243 | p = 0.2254 | |||
| OR = 1.462 | OR = 1.414 | OR = 1.463 | ||||
| 95% CI = 0.894 to 2.391 | 95% CI: 0.605 to 3.304 | 95% CI: 0.791to 2.706 | ||||
| Diplotype | ||||||
| H1H1 | 142 (64.5) | 94 (73.4) | 99 (65.5) | 22 (70.9) | 43 (62.3) | 72 (74.2) |
| H1H2 | 63 (28.6) | 23 (18.0) | 40 (26.5) | 7 (22.6) | 23 (33.3) | 16 (16.5) |
| H1Other | 10 (4.6) | 6 (4.7) | 8 (5.3) | 2 (6.5) | 2 (2.9) | 4 (4.1) |
| H2H2 | 4 (1.8) | 5 (3.9) | 3 (2.0) | 0 | 1 (1.5) | 5 (5.2) |
| OtherOther | 1 (0.5) | 0 | 1 (0.7) | 0 | 0 | 0 |
| Total | 220 | 128 | 151 | 31 | 69 | 97 |
| H1H2 v all others | p = 0.0190* | p = 0.6444 | p = 0.0096* | |||
| OR = 2.040 | OR = 1.242 | OR = 2.734 | ||||
| 95% CI: 1.124 to 3.7 | 95% CI: 0.494 to 3.123 | 95% CI: 1.277 to 5.852 | ||||
H1: GTC; H2: ACG.
Results: n (%)
*p<0.05
Discussion
Of the 22 studies listed on the www.alzgene.org website regarding polymorphisms in the BDNF gene associated with Alzheimer's disease, eight reported positive findings. The studies primarily involved the C270T and the rs6265 polymorphisms. Meta‐analysis reported on the same website (www.alzgene.org) of the seven studies of the C270T polymorphism using Caucasian subjects revealed odds ratios of 1.09 (95% CI: 0.7 to 1.68). However, meta‐analysis for the rs6265 (Val66Met) SNP in 11 studies of Caucasian subjects showed an odds ratio of 1.08 (95% CI: 0.98 to 1.19). Our study did not show any allelic association with the two polymorphisms with the T or A alleles. However, when additional SNPs were analysed, the combination of the heterozygous genotype of the rs6265 SNP with the heterozygous genotypes of the flanking SNPs (rs11030104 and rs2049045) was significantly associated with the disease in APOE 4 non‐carriers in our sample. To our knowledge we are the first group to examine the entire gene by genotyping all the tagSNPs as well as all the non‐synonymous SNPs currently listed. This strategy provided additional power to detect the association between the SNPs and the disease.
The gene for BDNF has been extensively studied recently and was found to consist of seven non‐coding exons and one major coding exon in type 1 BDNF and 11 exons of the reverse non‐coding type 2 BDNF gene.3 This assembly suggests multiple splicing patterns and transcripts providing heterogeneity in expression in different brain regions. The SNPs in our study are found between exons III and IV (rs11030121 and rs2049046), in exon V (C270T), between exon VIA and VII (rs2049045 and rs1130104), in the coding exon VIII (rs6265) and in the coding exon VIII after the polyadenylation site (rs7124442). The distance between rs2049045 and rs6265, including rs11030104, is approximately 14 308 bp. It is interesting that our analysis of the heterozygous genotypes of the three SNPs (rs6265:rs11030104:rs2049045; AG/CT/CG) produced an odds ratio of 2.57 (p = 0.0160; 95% CI: 1.193 to 5.55) in APOE 4 non‐carriers. Whether the two SNPs before exon VII are involved with alternative splicing of the VII/VIII transcript is unknown.
The BDNF Val66Met polymorphism has been associated with variations in the performance of episodic memory, with those carrying the Met allele performing worse than those homozygous for the Val genotype.27 In MRI studies of the hippocampus in healthy adults, those with the Val/Val genotypes had larger hippocampal volumes than those who carried the Val/Met genotypes.28,29,30,31 Heterozygous expression of the Val/Met genotypes formed heterodimers in cultured neurons which impaired regulated BDNF secretion.32 Since BDNF supports basal forebrain cholinergic projections to the hippocampus and neocortex, the downregulation of BDNF secretion may contribute to the neuronal loss found in Alzheimer's disease.
Electronic database information
The webpage of the Alzheimer Research Forum is at http://www.alzgene.org and details of the International HapMap Project can be found at http://www.hapmap.org
Acknowledgements
We thank the Texas and Georgia families for their active participation in the DNA Bank. DNA was also obtained from the National Cell Repository for Alzheimer's Disease.
Abbreviations
APOE - apolipoprotein E
BDNF - brain‐derived neurotrophic factor
Footnotes
This research was supported by MCG start‐up funds and by a cooperative agreement grant U24AG21886 from the National Institute of Aging for the National Cell Repository.
Competing interests: None declared.
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