Risk Polymorphisms of FNDC5, BDNF, and NTRK2 and Poor Education Interact and Aggravate Age-Related Cognitive Decline
Abstract
:1. Introduction
2. Results
2.1. Influence of Single Nucleotide Polymorphisms on Cognitive Performance
2.2. Age Affects Spatial Working Memory
Spatial Working Memory
- Subtitle: In the figure above, they are identified with “■”: the subjects with the highest risk in each group, and with “■”: the subjects with the lowest risk in each group. Each icon represents a sample subject. The black lines between the icons represent the means for each group. Squares are used to represent the BDNF gene, diamonds for the NTRK2 gene, and circles for the FNDC5 gene. On the left side of each graph are the groups with lower schooling (Young and Older), and on the right side are the groups with higher schooling (Young and Older). At the bottom of each graph, the number of participants in each group and their respective polymorphisms are highlighted.
2.3. For Sustained Visual Attention, the More Years of Study the Better the Cognitive Performance
Visual Sustained Attention—Rapid Visual Processing
- Subtitle: In the figure above, they are identified with “■”: the subjects with the highest risk in each group, and with “■”: the subjects with the lowest risk in each group. Each icon represents a sample subject. The black lines between the icons represent the means for each group. Squares are used to represent the BDNF gene, diamonds for the NTRK2 gene, and circles for the FNDC5 gene. On the left side of each graph are the groups with lower schooling (young and older), and on the right side are the groups with higher schooling (young and older). At the bottom of each graph, the number of participants in each group and their respective polymorphisms are highlighted.
2.4. Age and Higher Education Impact on Memory and Learning Performance
Learning and Memory—Paired Associated Learning
- Subtitle: In the figure above, they are identified with “■”: the subjects with the highest risk in each group, and with “■”: the subjects with the lowest risk in each group. Each icon represents a sample subject. The black lines between the icons represent the means for each group. Squares are used to represent the BDNF gene, diamonds for the NTRK2 gene, and circles for the FNDC5 gene. On the left side of each graph are the groups with lower schooling (young and older), and on the right side are the groups with higher schooling (young and older). At the bottom of each graph, the number of participants in each group and their respective polymorphisms are highlighted.
2.5. Reaction Time Increases with Aging Regardless of Education
Processing and Psychomotor Speed—Reaction Time
- Subtitle: In the figure above, they are identified with “■”: the subjects with the highest risk in each group, and with “■”: the subjects with the lowest risk in each group. Each icon represents a sample subject. The black lines between the icons represent the means for each group. Squares are used to represent the BDNF gene, diamonds for the NTRK2 gene, and circles for the FNDC5 gene. On the left side of each graph are the groups with lower schooling (young and older), and on the right side are the groups with higher schooling (young and older). At the bottom of each graph, the number of participants in each group and their respective polymorphisms are highlighted.
2.6. Recognition Memory Performance Worsens with Age and Improves with Education
Visual Recognition Memory—Delayed Matched to the Sample
- Subtitle: In the figure above, they are identified with “■”: the subjects with the highest risk in each group, and with “■”: the subjects with the lowest risk in each group. Each icon represents a sample subject. The black lines between the icons represent the means for each group. Squares are used to represent the BDNF gene, diamonds for the NTRK2 gene, and circles for the FNDC5 gene. On the left side of each graph are the groups with lower schooling (young and older), and on the right side are the groups with higher schooling (young and older). At the bottom of each graph, the number of participants in each group and their respective polymorphisms are highlighted.
3. Discussion
3.1. Education, Cognitive Reserve, and Aging
3.2. Genetic Polymorphisms Education and Senile Cognitive Decline
3.2.1. Val66Met (rs6265) of BDNF
3.2.2. NTRK2 (rs2289656)
3.2.3. FNDC5 (rs3840)
3.3. Limitations and Future Directions
4. Materials and Methods
4.1. Participants
4.2. Neuropsychological Assessment
4.3. DNA Extraction, Quantification, and Dilution
4.4. Analysis of Single Nucleotide Polymorphisms (SNPs)
4.5. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Groups | Young Lower Education | Young Higher Education | Older Lower Education | Older Higher Education | Total |
---|---|---|---|---|---|
SNP BDNF (rs6265) | CC: 46 CT + TT: 10 | CC: 39 CT + TT: 12 | CC: 28 CT + TT: 10 | CC: 37 CT + TT: 18 | CC: 150 CT + TT: 50 |
SNP NTRK2 (rs2289656) | GG: 31 AA + AG: 25 | GG: 31 AA + AG: 20 | GG: 22 AA + AG: 16 | GG: 27 AA + AG: 28 | GG: 111 AA + AG: 89 |
SNP FNDC5 (rs3840) | GG: 11 AA + AG: 45 | GG: 12 AA + AG: 39 | GG: 16 AA + AG: 22 | GG: 31 AA + AG: 24 | GG: 70 AA + AG: 130 |
Tests | Groups (n) | Mean ± SD | CI 95% | d | Age (F) | Education (F) | Interaction (F) |
---|---|---|---|---|---|---|---|
SWM strategy (score) | Young lower education (75) Older lower education (126) | −0.75 ± 1.04 0.44 ± 0.61 | −1.81, −1.17 *** | 1.49 | 270.60 *** | 0.14 | 1.91 |
Young lower education (75) Young higher education (75) | −0.75 ± 1.04 −0.89 ± 0.97 | −0.18, 0.46 | 0.14 | ||||
Young higher education (75) Older higher education (126) | −0.89 ± 0.97 0.52 ± 0.56 | 1.57, −2.25 *** | 1.91 | ||||
Older lower education (126) Older higher education (126) | 0.44 ± 0.61 0.52 ± 0.56 | −0.11, 0.38 | 0.14 | ||||
SWM total errors (score) | Young lower education (75) Older lower education (126) | −0.97 ± 0.82 0.61 ± 0.61 | 1.91, 2.63 *** | 2.27 | 503.41 *** | 0.23 | 0.36 |
Young lower education (75) Young higher education (75) | −0.97 ± 0.82 −0.96 ± 0.81 | −0.31, 0.33 | 0.01 | ||||
Young higher education (75) Older higher education (126) | −0.96 ± 0.81 0.53 ± 0.48 | −2.76, −2.02 *** | 2.39 | ||||
Older lower education (126) Older higher education (126) | 0.61 ± 0.61 0.53 ± 0.48 | −0.10, 0.39 | 0.15 |
Tests | Groups | Mean ± SD | CI 95% | d | Age (F) | Education (F) | Interaction (F) |
---|---|---|---|---|---|---|---|
RVP latency (ms) | Young lower education (75) Older lower education (126) | −0.58 ± 0.58 0.57 ± 0.96 | 1.05, 1.69 *** | 1.37 | 168.86 *** | 9.85 ** | 0.10 |
Young lower education (75) Young higher education (75) | −0.58 ± 0.58 −0.82 ± 0.46 | 0.13, 0.78 | 0.46 | ||||
Young higher education (75) Older higher education (126) | −0.82 ± 0.46 0.27 ± 0.96 | 1.03, 1.66 *** | 1.34 | ||||
Older lower education (126) Older higher education (126) | 0.57 ± 0.96 0.27 ± 0.96 | 0.06, 0.56 ** | 0.31 | ||||
RVP A’ (score) | Young lower education (75) Older lower education (126) | 0.46 ± 0.59 −0.57 ± 1.15 | 0.75, 1.35 *** | 1.05 | 104.92 *** | 14.10 *** | 1.27 |
Young lower education (75) Young higher education (75) | 0.46 ± 0.59 0.69 ± 0.49 | 0.10, 0.75 | 0.42 | ||||
Young higher education (75) Older higher education (126) | 0.69 ± 0.49 −0.12 ± 0.86 | 1.32, 1.98 *** | 1.65 | ||||
Older lower education (126) Older higher education (126) | 0.57 ± 1.15 −0.12 ± 0.86 | 0.19, 0.69 *** | 0.44 | ||||
RVP probability of hits (score) | Young lower education (75) Older lower education (126) | 0.37 ± 0.97 −0.47 ± 0.92 | 0.60, 1.19 *** | 0.89 | 98.84 *** | 13.61 *** | 0.42 |
Young lower education (75) Young higher education (75) | 0.37 ± 0.97 0.76 ± 0.78 | 0.12, 0.77 ** | 0.44 | ||||
Young higher education (75) Older higher education (126) | 0.76 ± 0.78 −0.20 ± 0.84 | 0.87, 1.48 *** | 1.17 | ||||
Older lower education (126) Older higher education (126) | −0.47 ± 0.92 −0.20 ± 0.84 | 0.06, 0.55 ** | 0.31 |
Tests | Groups | Mean ± SD | CI 95% | d | Age (F) | Education (F) | Interaction (F) |
---|---|---|---|---|---|---|---|
PAL total errors adjusted (score) | Young lower education (75) Older lower education (126) | −0.75 ± 0.34 0.69 ± 0.96 | 1.61, 2.39 *** | 2.00 | 268.72 *** | 10.93 ** | 4.09 * |
Young lower education (75) Young higher education (75) | −0.75 ± 0.34 −0.85 ± 0.24 | 0.02, 0.66 | 0.34 | ||||
Young higher education (75) Older higher education (126) | −0.85 ± 0.24 0.27 ± 0.91 | 1.20, 1.84 *** | 1.52 | ||||
Older lower education (126) Older higher education (126) | 0.69 ± 0.96 0.27 ± 0.91 | 0.20, 0.70 *** | 0.45 | ||||
PAL mean trials to success (score) | Young lower education (75) Older lower education (126) | −0.81 ± 0.40 0.71 ± 0.87 | 1.25, 1.90 *** | 1.57 | 349.64 *** | 10.37 *** | 2.83 |
Young lower education (75) Young higher education (75) | −0.81 ± 0.40 −0.93 ± 0.31 | 0.01, 0.66 | 0.34 | ||||
Young higher education (75) Older higher education (126) | −0.93 ± 0.31 0.34 ± 0.87 | 1.44, 2.11 *** | 1.78 | ||||
Older lower education (126) Older higher education (126) | 0.71 ± 0.87 0.34 ± 0.87 | 0.18, 0.54 *** | 0.42 | ||||
PAL first trial memory score (score) | Young lower education (75) Older lower education (126) | 0.73 ± 0.75 −0.66 ± 0.74 | 1.53, 2.21 *** | 1.87 | 286.87 *** | 10.67 *** | 0.99 |
Young lower education (75) Young higher education (75) | 0.73 ± 0.75 0.91 ± 0.80 | −0.09, 0.55 | 0.23 | ||||
Young higher education (75) Older higher education (126) | 0.91 ± 0.80 −0.32 ± 0.73 | 1.30, 1.95 *** | 1.63 | ||||
Older lower education (126) Older higher education (126) | −0.66 ± 0.74 −0.32 ± 0.73 | 0.21, 0.71 *** | 0.46 |
Tests | Groups | Mean ± SD | CI 95% | d | Age (F) | Education (F) | Interaction (F) |
---|---|---|---|---|---|---|---|
RTI simple accuracy score (score) | Young lower education (75) Older lower education (126) | 0.22 ± 0.43 −0.21 ± 1.16 | 0.16, 0.74 ** | 0.45 | 24.87 *** | 1.28 | 0.44 |
Young lower education (75) Young higher education (75) | 0.22 ± 0.43 0.40 ± 0.28 | 0.17, 0.82 | 0.50 | ||||
Young higher education (75) Older higher education (126) | 0.40 ± 0.28 −0.16 ± 1.22 | 0.28, 0.86 *** | 0.57 | ||||
Older lower education (126) Older higher education (126) | −0.21 ± 1.16 −0.16 ± 1.22 | −0.20, 0.29 | 0.04 | ||||
RTI five-choice accuracy score (score) | Young lower education (75) Older lower education (126) | 0.09 ± 0.70 −0.15 ± 1.29 | −0.07, 0.50 | 0.22 | 10.73 *** | 2.10 | 0.71 |
Young lower education (75) Young higher education (75) | 0.09 ± 0.70 0.32 ± 0.39 | 0.08, 0.73 | 0.41 | ||||
Young higher education (75) Older higher education (126) | 0.32 ± 0.39 −0.09 ± 1.02 | 0.23, 0.62 ** | 0.50 | ||||
Older lower education (126) Older higher education (126) | −0.15 ± 1.29 −0.09 ± 1.02 | −0.27, 0.37 | 0.05 |
Tests | Groups | Mean ± SD | CI 95% | d | Age (F) | Education (F) | Interaction (F) |
---|---|---|---|---|---|---|---|
RTI simple movement time (ms) | Young lower education (75) Older lower education (126) | −0.29± 0.40 0.18± 0.48 | 0.74, 1.34 | 1.04 | 22.93 *** | 0.01 | 0.001 |
Young lower education (75) Young higher education (75) | −0.29± 0.40 −0.31 ± 0.29 | −0.26, 0.38 | 0.06 | ||||
Young higher education (75) Older higher education (126) | −0.31 ± 0.29 0.17± 1.62 | 0.08, 0.66 | 0.37 | ||||
Older lower education (126) Older higher education (126) | 0.18± 0.48 0.17± 1.62 | −0.24, 0.26 | 0.01 | ||||
RTI five-choice movement time (ms) | Young lower education (75) Older lower education (126) | −0.47± 0.71 0.56± 1.05 | 0.79, 1.40 | 1.10 | 89.47 *** | 9.23 ** | 2.79 |
Young lower education (75) Young higher education (75) | −0.47± 0.71 −0.60 ± 0.54 | −0.11, 0.53 | 0.21 | ||||
Young higher education (75) Older higher education (126) | −0.60 ± 0.54 0.12 ± 0.97 | 0.56, 1.16 | 0.86 | ||||
Older lower education (126) Older higher education (126) | 0.56± 1.05 0.12 ± 0.97 | 0.19, 0.69 | 0.44 | ||||
RTI simple reaction time (ms) | Young lower education (75) Older lower education (126) | −0.29 ± 0.59 0.21± 1.00 | −0.73, −0.28 | 0.58 | 37.09 *** | 0.47 | 0.98 |
Young lower education (75) Young higher education (75) | −0.29± 0.59 −0.46± 0.49 | −0.01, 0.64 | 0.31 | ||||
Young higher education (75) Older higher education (126) | −0.46± 0.49 0.24 ± 1.24 | 0.38, 0.96 | 0.67 | ||||
Older lower education (126) Older higher education (126) | 0.21± 1.00 0.24 ± 1.24 | −0.22, 0.27 | 0.03 | ||||
RTI five-choice reaction time (ms) | Young lower education (75) Older lower education (126) | −0.36± 0.70 0.36 ± 1.06 | 0.47, 1.06 | 0.76 | 72.70 *** | 3.27 | |
Young lower education (75) Young higher education (75) | −0.36 ± 0.70 −0.63 ± 0.71 | 0.06, 0.71 | 0.38 | ||||
Young higher education (75) Older higher education (126) | −0.63 ± 0.71 0.28 ± 0.97 | 0.73, 1.33 | 1.03 | ||||
Older lower education (126) Older higher education (126) | 0.36 ± 1.06 0.28 ± 0.97 | −0.24, 0.40 | 0.08 |
Tests | Groups | Mean ± SD | CI 95% | d | Age (F) | Education (F) | Interaction (F) |
---|---|---|---|---|---|---|---|
DMS probability of error given correct (score) | Young lower education (75) Older lower education (126) | −0.45 ± 0.68 0.57 ± 1.04 | 0.80, 1.41 *** | 1.11 | 150.03 *** | 4.24 * | 1.33 |
Young lower education (75) Young higher education (75) | −0.45 ± 0.68 −0.74 ± 0.46 | 0.17, 0.82 * | 0.50 | ||||
Young higher education (75) Older higher education (126) | −0.74 ± 0.46 0.49 ± 0.92 | 1.25, 1.90 *** | 1.57 | ||||
Older lower education (126) Older higher education (126) | 0.57 ± 1.04 0.49 ± 0.92 | −0.17, 0.33 | 0.08 | ||||
DMS probability of error given error (score) | Young lower education (75) Older lower education (126) | −0.35 ± 0.86 0.45 ± 1.09 | 0.50, 1.09 *** | 0.79 | 43.76 *** | 5.16 * | 0.09 |
Young lower education (75) Young higher education (75) | −0.35 ± 0.86 −0.57 ± 0.62 | −0.03, 0.62 | 0.29 | ||||
Young higher education (75) Older higher education (126) | −0.57 ± 0.62 0.15 ± 0.93 | 0.57, 1.17 *** | 0.87 | ||||
Older lower education (126) Older higher education (126) | 0.45 ± 1.09 0.15 ± 0.93 | 0.05, 0.54 * | 0.30 | ||||
DMS total correct (score) | Young lower education (75) Older lower education (126) | 0.48 ± 0.73 −0.65 ± 0.90 | 1.03, 1.66 *** | 1.34 | 196.00 *** | 7.67 ** | 0.93 |
Young lower education (75) Young higher education (75) | 0.48 ± 0.73 0.81 ± 0.49 | 0.21, 0.86 ** | 0.53 | ||||
Young higher education (75) Older higher education (126) | 0.81 ± 0.49 −0.49 ± 0.88 | 1.38, 2.04 *** | 1.71 | ||||
Older lower education (126) Older higher education (126) | −0.65 ± 0.90 −0.49 ± 0.88 | −0.07, 0.43 | 0.18 |
Groups | Young Lower Education (YLE) | Young Higher Education (YHE) | Older Lower Education (OLE) | Older Higher Education (OHE) |
---|---|---|---|---|
Participants (n) | 75 | 75 | 126 | 126 |
Age (years) | 25.49 ± 2.32 | 26.98 ± 2.12 | 70.79 ± 2.25 | 69.55 ± 2.35 |
Sex (n) | Female: 37 Male: 38 | Female: 36 Male: 39 | Female: 102 Male: 24 | Female: 99 Male: 27 |
MMSE (points) | 29.04 ± 1.60 | 29.23 ± 0.83 | 27.00 ± 2.27 | 28.32 ± 1.25 |
Education (years) | 12.94 ± 1.60 | 17.66 ± 1.37 | 5.22 ± 1.38 | 12.14 ± 1.57 |
Gene/rs | Vic/Fam Fluorophores | Localization | Outcomes |
---|---|---|---|
BDNF/rs6265 | C/T | Chr.11: 27658369 | T allele associated with memory impairment 1, increases susceptibility to developing Alzheimer’s disease 2. Associated with reduced hippocampal volume 3. |
NTRK2/rs2289656 | A/G | Chr.9: 84948647 | G allele, lower risk of cognitive impairment 4. Patients with Alzheimer’s disease are more frequently heterozygous for this gene 5. |
FNDC5/rs3480 | A/G | Chr.1: 32862564 | G allele associated with reduced expression, greater susceptibility to diabetes mellitus, and its metabolic dysfunctions 6. |
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© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Tomás, A.M.; Bento-Torres, N.V.O.; Jardim, N.Y.V.; Moraes, P.M.; da Costa, V.O.; Modesto, A.C.; Khayat, A.S.; Bento-Torres, J.; Picanço-Diniz, C.W. Risk Polymorphisms of FNDC5, BDNF, and NTRK2 and Poor Education Interact and Aggravate Age-Related Cognitive Decline. Int. J. Mol. Sci. 2023, 24, 17210. https://doi.org/10.3390/ijms242417210
Tomás AM, Bento-Torres NVO, Jardim NYV, Moraes PM, da Costa VO, Modesto AC, Khayat AS, Bento-Torres J, Picanço-Diniz CW. Risk Polymorphisms of FNDC5, BDNF, and NTRK2 and Poor Education Interact and Aggravate Age-Related Cognitive Decline. International Journal of Molecular Sciences. 2023; 24(24):17210. https://doi.org/10.3390/ijms242417210
Chicago/Turabian StyleTomás, Alessandra Mendonça, Natáli Valim Oliver Bento-Torres, Naina Yuki Vieira Jardim, Patrícia Martins Moraes, Victor Oliveira da Costa, Antônio Conde Modesto, André Salim Khayat, João Bento-Torres, and Cristovam Wanderley Picanço-Diniz. 2023. "Risk Polymorphisms of FNDC5, BDNF, and NTRK2 and Poor Education Interact and Aggravate Age-Related Cognitive Decline" International Journal of Molecular Sciences 24, no. 24: 17210. https://doi.org/10.3390/ijms242417210