Neurotrophin

Single Nucleotide Polymorphisms and Cognitive Functioning in Older Adults:

The Cache County Study.
J Matyi, BS1, J Kauwe, PhD2, C Sanders, BS1, GB Rattinger, PharmD, PhD3, C Corcoran, ScD1,
M Norton, PhD1, R Munger, PhD MPH1, M Buhusi, MD, PhD1, & JT Tschanz, PhD1
1 Utah State University, Logan, UT, USA, 2 Brigham Young University, Provo, UT, USA, 3 Fairleigh Dickinson University, School of Pharmacy, Florham Park, NJ, USA

Abstract Methods R e s u l t s (cont.)

Background: Neurotrophins are critically important in regulating neural processes such as Participants: Table 1: SNP genotype frequencies by sex
Male Female
synaptogenesis, synaptic plasticity and neuronal survival in developing, adult, and aged From the Cache Country Memory Study, 4746 individuals, aged 65+ and 57% female, SNP N Percent N Percent
rs2072446
brains. Dysfunction in neurotrophin processing has been implicated in Alzheimers were followed approximately every 3-4 years for a maximum of 11 years C/C
C/T
1840
158
91.9
7.9
2463
211
91.6
7.8
disease (AD) and may be linked to late-life cognitive decline. We examined the T/T 5 0.2 14 0.5
Mean (SD) age at baseline was 75.97 (7.14) rs2020918
association of five single nucleotide polymorphisms (SNPs) in neurotrophin and C/C
C/T
816
875
42.1
45.2
1148
1135
43.9
43.4
neurotrophin receptor genes with cognitive functioning in a population-based sample of Procedures: T/T
rs2289656
245

12.7 334 12.8

older adults. Blood and buccal cell samples were obtained for genotyping through four triennial
C/C
C/T
1362
560
68.3
28.1
1775
796
66.4
29.8
T/T 73 3.7 103 3.9
Methods: 4746 individuals (aged 65+, 57% female) were followed every 3-4 years for a waves (1995 2007) rs56164415
C/C

1763 88.5 2368 88.9

maximum of 11 years. Mean (SD) age at baseline was 75.97 (7.14). Genotypes were Using standard TaqMan Assays from Life Technologies, genotypes were identified for
C/T
T/T
229
0
11.5
0
295
0
11.1
0

available for the following SNPs: rs6265 (BDNF G196A/Val66Met), rs56164415 (BDNF the following SNPs: rs6265 (BDNF G196A/Val66Met); rs56164415 (BDNF C270T);
rs6265
G/G

1340 66.3 1758 64.7
G/A 601 29.7 839 30.9
C270T), rs2289656 (BDNF receptor TrkB), rs2072446 (NGF receptor TrkA), and rs2020918 rs2289656 (BDNF receptor TrkB); rs2072446 (NGF receptor TrkA); and rs2020918 (TPA) A/A 81 4 122 4.5

(TPA). Cognitive status was assessed at baseline and during three triennial follow-ups (see Table 1) Figure 1: Association of BDNF receptor TrkB (rs2289656) genotype with cognitive decline
using the Modified Mini-Mental State Examination (3MS). We used linear mixed effects varies by age in females
Measures:
models to examine the association between genotypes and 3MS scores and tested age,
education, and APOE genotype as covariates. Males and females were examined in Cognitive Decline
separate models. An adapted version of the Modified Mini-Mental State Examination (3MS) was used to
Results: Higher 3MS scores were associated with the A/G genotype of rs6265 (BDNF assess cognitive status at baseline and during three triennial follow-ups
Val66Met; B=1.06, SE=.4) in females and T/C genotype of rs2072446 (NGF receptor TrkA; The 3MS includes items assessing orientation, registration, attention and calculation,
B=1.82, SE=.77) in males, although neither association remained significant after memory recall, and language; scores range from 0 - 100 9
controlling for age. There was a significant age by genotype interaction (p=.04) for Genotypes
rs2289656 (BDNF receptor TrkB) in females in which the C/C genotype was associated
with higher 3MS scores in younger but not older participants. There was no association BDNF: rs6265 (BDNF G196A/Val66Met) = G/G; A/A; A/G
between rs56164415 (BDNF) and rs2020918 (TPA) genotypes and 3MS. rs56164415 (BDNF C270T) = C/C; C/T; T/T
rs2289656 (BDNF receptor TrkB) = C/C; C/T; T/T
Conclusions
Conclusions: Three of the five neurotrophin-related SNPs examined showed associations
with cognition in a population-based sample of older adults, but results with BDNF NGF: rs2072446 (NGF receptor TrkA) = C/C; C/T; T/T We report that the association of selected SNPs in the BDNF neurotrophin pathway and
rs6265 and TrkA rs2072446 were confounded by age and varied by gender. Our finding of cognitive decline differ by sex and in some cases, with age (TrkB rs2289656)
TPA: rs2020918 (TPA) = C/C; C/T; T/T
higher cognitive functioning for the TrkB rs2289656 C/C genotype is consistent with that Two SNPs (rs6265 and rs2072446) were associated with cognitive function in males or
of lower risk of AD in an Italian sample; however, we found a protective effect only in Statistical Modeling:
females, respectively, but were confounded by age
younger females. The current analyses underscore the importance of considering sex and Linear mixed models (random slopes and intercepts) examined associations between
The higher cognitive functioning for the TrkB rs2289656 C/C genotype in younger Cache
age when examining the effects of genes that code for neurotrophins or neurotrophin genotype and 3MS scores over time and tested age, education, and APOE genotype as
County females is consistent with the finding of lower risk of AD in an Italian sample
receptors. covariates
(mean age younger than Cache County sample)
Separate models were run for males and females
Introduction Sex-related and age-related differences observed here may explain some of the
contradictory findings in the literature
Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin involved in many critical Results Future research is needed to examine individual differences (sex, age) and
brain processes across the lifespan such as synaptogenesis, synaptic plasticity and environmental exposures (gene*environment interactions) that affect the association of
neuronal survival 1, 2, 3 neurotrophins and neurotrophin receptors on cognitive decline in late life
Males:
BDNF has been associated with various neuropsychiatric diseases including cognitive
The T/C genotype of rs2072446 (NGF receptor TrkA; B=1.82, SE=.77) was associated with
impairment and Alzheimers disease (AD), however, these results are not consistent
higher 3MS scores in males but did not remain significant after controlling for age
Citations
across studies 4, 5, 6 1. Reichardt, L. F. (2006). Neurotrophin-regulated signaling pathways. Philosophical Transactions of the Royal Society of London
Females: B: Biological Sciences, 361(1473), 1545-1564.
Several functional single nucleotide polymorphisms (SNPs) have been identified in the 2. Greenberg, M. E., Xu, B., Lu, B., & Hempstead, B. L. (2009). New insights in the biology of BDNF synthesis and release:
BDNF, Nerve Growth Factor (NGF), and Tissue Plasminogen Activator (TPA) pathways: The A/G genotype of rs6265 (BDNF Val66Met; B=1.06, SE=.4) was associated with higher implications in CNS function. The Journal of neuroscience, 29(41), 12764-12767.
rs6265 (BDNF G196A/Val66Met); rs56164415 (BDNF C270T); rs2289656 (BDNF receptor 3MS scores in females but did not remain significant after controlling for age 3. Lu, B., Pang, P. T., & Woo, N. H. (2005). The yin and yang of neurotrophin action. Nature Reviews Neuroscience, 6(8), 603-614.
4. Diniz, B. S., & Teixeira, A. L. (2011). Brain-derived neurotrophic factor and Alzheimers disease: physiopathology and
TrkB); rs2072446 (NGF receptor TrkA); and rs2020918 (TPA) 5, 6, 7, 8 There was a significant age by genotype interaction (p=.04) for rs2289656 (BDNF beyond. Neuromolecular medicine, 13(4), 217-222.
5. Lin, Y., Cheng, S., Xie, Z., & Zhang, D. (2014). Association of rs6265 and rs2030324 polymorphisms in brain-derived
A recent meta-analysis suggests sex differences in associations between BDNF SNPs and receptor TrkB) in females where the C/C genotype was associated with higher 3MS neurotrophic factor gene with Alzheimers disease: a meta-analysis. PloS one, 9(4), e94961.
risk for AD 5 scores in younger but not older participants (see Figure 1) 6. Chuu, J. Y., Taylor, J. L., Tinklenberg, J., Noda, A., Yesavage, J., & Murphy Jr, G. M. (2006). The brain-derived neurotrophic factor
Val66Met polymorphism and rate of decline in Alzheimer's disease. Journal of Alzheimer's disease: JAD, 9(1), 43-49.
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Objective: To examine the associations between five functional BDNF There were no significant associations between rs56164415 (BDNF) and rs2020918 (TPA) 8. Pang, P. T., Teng, H. K., Zaitsev, E., Woo, N. T., Sakata, K., Zhen, S., ... & Lu, B. (2004). Cleavage of proBDNF by tPA/plasmin is
SNP genotypes and late-life cognitive decline in the Cache County Study genotypes and 3MS scores in either males or females essential for long-term hippocampal plasticity. Science, 306(5695), 487-491.
9. Lee Teng, E., & Chang Hui, H. (1987). The modified mini-mental state (3MS) examination. The Journal of Clinical
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***Supported by NIH grants: R01AG11380, R01AG18712, and R01AG21136***
decline in late life