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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 62:196-201 (2007)
© 2007 The Gerontological Society of America

Methylenetetrahydrofolate Reductase 677C>T and Methionine Synthase 2756A>G Mutations: No Impact on Survival, Cognitive Functioning, or Cognitive Decline in Nonagenarians

Lise Bathum, Jacob von Bornemann Hjelmborg, Lene Christiansen, Matt McGue, Bernard Jeune and Kaare Christensen

1 Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Denmark.
Departments of 2 Epidemiology and 3 Statistics, Institute of Public Health, University of Southern Denmark, Odense.
4 Department of Psychology, University of Minnesota, Minneapolis.

Address correspondence to Lise Bathum, MD, PhD, Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, DK-5000 Odense C, Denmark. E-mail: lisebathum{at}dadlnet.dk


   Abstract
Top
 Abstract
Participants and Methods
 Results
 Discussion
 References
 
Background. Several reports have shown an association between homocysteine, cognitive functioning, and survival among the oldest-old. Two common polymorphisms in the genes coding for methylenetetrahydrofolate reductase (MTHFR 677C>T) and methionine synthase (MTR 2756A>G) have an impact on plasma homocysteine level.

Methods. We examined the effect of the MTHFR 677C>T and MTR 2756A>G genotypes on baseline cognitive functioning, cognitive decline over 5 years measured in three assessments, and survival in a population-based cohort of 1581 nonagenarians. Cognitive functioning was assessed by using the Mini-Mental State Examination (MMSE) and five brief cognitive tests (cognitive composite).

Results. There are no differences in MMSE score (p =.83) or in cognitive composite (p =.56) at intake as a function of genotype tested by analysis of variance, whereas sex and social group have a impact on MMSE (p ≤.03), and social group on the cognitive composite (p <.01). The mean MMSE was lower for women than for men. However, considering the group participating in all three assessments, there were no sex-related differences in MMSE (p =.34). The cognitive decline in the group participating in all three assessments was investigated using regression models for the relationship between cognitive performance and genotype, age, sex, and social group and revealed no significant difference. Furthermore, the MTHFR 677T and MTR 2756A heterozygous and homozygous genotype had no significant impact on survival, with hazard ratios of 1.05 (95% confidence interval [CI], 0.93–1.17), 0.93 (95% CI, 0.77–1.14), 1.05 (95% CI, 0.94–1.18), and 0.97 (95% CI, 0.74–1.28).

Conclusions. MTHFR and MTR genotypes are not associated with cognitive functioning, cognitive decline, or survival among nonagenarians.

Cognitive functioning is central in successful aging and longevity. Cognition has been shown to be associated with mortality in several studies among younger elderly persons (1). Although many factors such as marital status, smoking status, and education (with proven influence on mortality among younger elderly persons) apparently lose their importance in the oldest-old, cognitive functioning and other measures of current resources are still strong predictors of mortality among the oldest-old (2). Several reports have shown an association between homocysteine (a sulfur-containing amino acid), cognitive functioning, and survival among the oldest-old (3–5). Plasma total homocysteine has been associated with cardiovascular events and cardiovascular mortality in men (6) and women (7,8), including a strong association with all-cause mortality in elderly persons (5,9,10). The mechanism for the effect of homocysteine on cognitive decline and whether homocysteine itself is the toxic compound is largely unknown. However, it is quite clear that high homocysteine concentrations predicts cognitive decline (11–13).

Homocysteine is formed during the metabolism of the essential amino acid methionine, and three different metabolic pathways are involved: remethylation of homocysteine to methionine catalyzed by the enzyme methylenetetrahydrofolate reductase (MTHFR), transmethylation from methyltetrahydrofolate to homocysteine catalyzed by methionine synthase (MTR), and transsulfuration. The underlying causes for increased homocysteine are both genetic and nutritional (14). Dietary intake of folate, vitamin B12, and vitamin B6 certainly play a role in combination with genetic factors (15). Furthermore, several physiologic and lifestyle factors and common diseases influence plasma levels of homocysteine. Increasing age, male sex, smoking status, coffee consumption, high blood pressure, unfavorable lipid profile, impaired kidney function, physical activity, and alcohol consumption are among factors influencing homocysteine levels (16).

It is well known that a common polymorphism in the MTHFR gene (677C>T) has a pronounced impact on plasma homocysteine level. As T allele dose increases, this functional polymorphism causes a graded elevation in homocysteine in the mild-to-moderate range, most pronounced in individuals with low dietary folate consumption (17). A common polymorphism in the MTR gene (2756A>G) also seems to influence plasma homocysteine with the A-allele and the AA genotype associated with elevated homocysteine concentration (18). Whereas there is reasonable agreement that plasma homocysteine influences cognition and survival among the oldest-old (19), the results concerning the MTHFR polymorphism are contradictory (20–24), and the influence of the MTR polymorphism has only been sparsely investigated (18).

If homocysteine is in fact a toxic compound that influences cognition and survival among the oldest-old, the two common polymorphisms in MTHFR and MTR with proven influence on homocysteine levels should be associated as well. Using a study of the entire Danish 1905 Cohort, we have genotyped 1581 individuals for these two polymorphisms and related the results to cognitive functioning at intake, cognitive decline, and survival.


   PARTICIPANTS AND METHODS
Top
 Abstract
 Participants and Methods
Results
 Discussion
 References
 
Participants and Measurement of Cognitive Abilities
The participants in this study were from the Danish 1905 Cohort—a study of all Danes born in 1905 ascertained in 1998 when they were 92–93 years old (25). The survivors were reassessed in 2000 and 2003. A total of 3600 persons were approached in 1998, and 2262 persons participated: 1814 in person and 448 via a proxy responder. The main reason for participation via a proxy was dementia (58%). The participants were invited to participate in a home-based 2-hour interview including cognitive and physical performance tests as well as collection of DNA (25). Cognitive functioning was assessed with the Mini-Mental State Examination (MMSE) (26) and five brief individual tests of cognitive functioning (27). The MMSE is a widely used screen designed to primarily differentiate cognitive impairment from normal cognitive functioning among the oldest-old. The MMSE yields a score between 0 and 30. Cognitive impairment is graded as severe for scores between 0 and 17, mild for scores between 18 and 23, and normal for scores between 24 and 30. The five brief individual tests of cognitive functioning are designed to detect different levels of healthy cognitive functioning, and include a fluency task (number of animals the individual can name within 1 minute), forward and backward digit span, and immediate and delayed recall, which lasts approximately 15 minutes, while participants completed other noncognitive assessments, of a 12-item list. To facilitate interpretation of results, each of the five brief individual tests of cognitive functioning was standardized to a mean of 0 and a standard deviation of 1 in the total sample before summing into one cognitive composite score (27). Because the scaling for the MMSE is well known, a similar transformation of this variable was not done.

Cognitive functioning was assessed, and DNA samples were collected only from participants who were able to perform our interview without help of a proxy. The DNA sample could either be given as a bloodspot or a cheek-swab. The regional Scientific Ethical Committees of Denmark approved the survey (Case No. 19980073). All participants provided consent to participate before the interview. The genotyping for the two selected genes has been approved by the Regional Committee of Vejle and Funen Counties.

Determination of MTHFR and MTR Genotype
DNA was isolated from cheek swabs and blood spots with the use of the QIAamp DNA Mini Kit (Qiagen, Hilden, Germany). TaqMan technology was used to genotype the two polymorphisms in MTHFR (677C>T) and MTR (2756A>G). Primers and probes were designed using Primer Express software (Applied Biosystems, Foster City, CA). Primers and probes used were (for MTHFR): sense 5'-GACCTGAAGCACTTGAAGGAGAA-3', antisense 5'-TGTGTCAGCCTCAAAGAAAAGC-3', C-allele probe 5'-FAM-ATGATGAAATCGGCTCCCGCA-Tamra-3', T-allele probe 5'-TET-TGATGATGAAATCGACTCCCGCA-Tamra-3' and (for MTR): sense 5'-GAGGAAATCATGGAAGAATATGAAGAT-3', antisense 5'-AAATCTGTTTCTACCACTTACCTTGAGA-3', A-allele probe 5'-FAM-ACTCATAATGGTCCTGTCTAA-NFQ-3', G-allele probe 5'-VIC-TCATAATGGCCCTGTCTAA-NFQ-3'. The probes used for genotyping MTR contained minor groove binder groups attached to their 3' ends. Allele discrimination was performed with an ABI PRISM 7700 Sequence Detection System equipped with the allelic discrimination module (software version 1.7; Applied Biosystems).

Statistical Analysis
The distribution of genotypes and the presence of Hardy–Weinberg equilibrium were tested by a chi-square test. To compare mean MMSE and cognitive composite score at intake according to MTHFR and MTR genotype as well as sex and social status, we used an analysis of variance. The effect of MTHFR and MTR genotype on change in cognitive functioning was investigated using marginal regression models for the relationship between cognitive performance (either the composite or MMSE) and MTHFR or MTR genotype, age, sex, and socioeconomic status (28). Occupational titles were coded for socioeconomic status on a 5-point scale ranging from 1 = higher professional (e.g., has more 20 subordinates, university professor) to 5 = unskilled laborer. Full-time homemakers were coded as 6. As 31% females reported that they were housewives and 72% reported that they have no education after primary school, we used the socioeconomic status of the spouse in the analysis, if it was higher than the participant's status.

The participants were followed from the date of blood sampling and until emigration, death, or end of study period (January 10, 2006). Information on emigration and death was retrieved from the Danish Central Population Register, which is continuously updated. Cox regression analysis was used for the survival analysis. A hazard ratio of 1.00 indicates the reference category; the homozygous wild-type genotype (C677CC or 2756AA) was chosen as the reference category. The statistical program package Stata (release 8.0; StataCorp., College Station, TX) was used for the statistical calculation.


   RESULTS
Top
 Abstract
 Participants and Methods
 Results
Discussion
 References
 
Genotype Distribution
The genotype distributions are shown in Table 1. The two genes are located on the same chromosome; MTHFR is positioned at 1p36.3 and MTR at 1q43; however, the distance makes it unlikely that the two genes are inherited as a unit. The distributions are as expected for two independently inherited single nucleotide polymorphisms (SNPs) (p =.31 for men and p =.98 for women), thereby confirming no interaction between the distribution of MTHFR and MTR genotypes. The distributions are in Hardy–Weinberg equilibrium (p =.55 for MTR and p =.27 for MTHFR). The genotype distribution in the group participating in all three waves is comparable to the distribution in the group participating at intake and the dropout due to death, interview by proxy, or nonparticipation (p >.72 for both men and women).


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  		Table 1. Basic Description of the Study Population: Data From the 1651 Participants Who Provided a DNA Sample.

 
Relationship Between Cognitive Functioning at Intake and Genotype
Table 1 presents the mean MMSE scores at intake. There are no genotype-specific differences in MMSE score (p =.83 for MTHFR and p =.56 for MTR) or in cognitive composite (p =.99 for MTHFR and p =.77 for MTR) looking at the two SNPs isolated. However, sex has a significant impact on MMSE, with men having the higher scores (p =.03) but not on the cognitive composite (p =.68). Social group had a significant contribution to both MMSE and cognitive composite (p <.01). When restricting the analysis to the group participating in all three assessments, sex had no impact on MMSE (p =.34).

Relationship Between Cognitive Decline and Genotype
Initially, we tested whether the different cognitive groups were comparable (Figure 1), looking at the three outcome groups: participating in all three waves; participating at intake and wave 1, and then dropping out; and participating at intake and then dropping out. Figure 1 show that these three groups are not comparable and that data at intake are influenced by outcome. Dropout was almost entirely due to death or needing a proxy respondent (14% at first follow-up and 24% at second follow-up). As the reason for needing a proxy respondent was dementia in 41% in the first follow-up and 56% in the second follow-up, we chose to restrict the analyses to a standard regression on data from the group participating in all three waves.


Figure 01
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  		Figure 1. Mean Mini-Mental State Examination (MMSE) score versus mean age for the three measurements in each individual with a DNA sample. The group with one measurement was only participating at intake; two measurements were participating at intake and first follow-up, three measurements participated at all three assessments. No measurement is due to death, need for a proxy respondent, or nonparticipation

 
The response profiles for mean MMSE score versus mean age for the three measurements divided into the three MTHFR 677C>T genotype groups are shown in Figure 2 and divided into the three MTR 2756A>G genotype groups in Figure 3. Test statistics from the regression models are shown in Table 2. To adjust for correlation between several observations on the same participant, robust estimates of standard errors and hence confidence intervals were estimated (using Stata's cluster option). Furthermore, a linear regression was performed, taking the first and the second cognitive measurements into consideration together with MTHFR or MTR genotype, age, and sex. Analyses including only the first and second measurement did not change the results (p >.4 for all analyses). As can be seen from Table 2 and Figures 2 and 3, there are no differences between cognitive declines in the three genotype groups.


Figure 02
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  		Figure 2. Profiles for mean Mini-Mental State Examination (MMSE) score versus mean age for the three measurements in each individual with a DNA sample divided in the three methylenetetrahydrofolate reductase (MTHFR) genotype groups. Only complete cases are included

 

Figure 03
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  		Figure 3. Profiles for mean Mini-Mental State Examination (MMSE) score versus mean age for the three measurements in each individual with a DNA sample divided into the three methionone synthase (MTR) genotype groups. Only complete cases are included

 

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  		Table 2. Test Statistics From the Regression Models.

 
Relationship Between Survival and Genotype
The results from the Cox regression model stratified for sex including the covariates sex, social status, and MMSE score are shown in Table 3. No indication of violation of the proportional hazards assumption was observed from standard methods. MMSE scores do have a significant influence on survival—the hazard decreases 5% for each increase in MMSE score. However, social status and MTHFR and MTR genotypes have no significant influence on survival probability.


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  		Table 3. Data From Survival Analysis.

 

   DISCUSSION
Top
 Abstract
 Participants and Methods
 Results
 Discussion
References
 
Numerous studies have established that an elevated plasma concentration of homocysteine is associated with decreased cognitive functioning and survival among the oldest-old (3,5,29). Since two common mutations in the MTHFR and MTR genes frequently cause hyperhomocysteinemia, they are suspected to influence cognitive functioning. However, our results do not find any association between these genotypes and baseline cognitive functioning or cognitive decline over 5 years. In a previous study by Durga and colleagues (30), researchers found better cognitive performance in participants with the MTHFR 677TT genotype compared to the 677CT/CC genotypes. This result is surprising because the 677TT genotype is associated with increased homocysteine levels. Furthermore, most other studies found no association between MTHFR genotypes and cognition (20, 21,23). This apparent contradiction could be due to the fact that the study of Durga and colleagues included only participants with normal homocysteine levels and therefore excluded the worst performing MTHFR 677TT. The relationship between the MTR 2756A>G polymorphism and cognition has only been sparsely tested, but one study found that the MTR 2756AA genotype is a risk factor for Alzheimer's disease (18), which is not in accordance with our results. However, the results of ours and previous studies do not exclude that the MTHFR 677C>T and MTR 2756A>G mutations under certain circumstances may predispose to cognitive impairment and premature death. The effect of the tested mutations could be different in different populations as the effect is probably related to folate status. It has been shown that the MTHFR 677TT genotype results in elevated homocysteine concentrations almost only in participants with a concomitant poor folate status (15,31).

The fact that DNA samples were not collected from participants interviewed by proxy could introduce a bias, as the main reason (58%) for interview by proxy at intake was dementia. This fact might explain the absence of an effect in the cross-sectional analysis. However, the study is longitudinal with three cognitive measurements over 5 years. The fact that there is no genotype-related influence on cognitive decline over these 5 years makes an influence of the selected genotypes on cognitive functioning in this age group very unlikely. Furthermore, dropout is genotype-independent as there is no difference in genotype distribution between the group participating in all three waves and the group participating at intake and then dropping out (due to death, need for a proxy respondent, or nonparticipation).

It is debated whether homocysteine exerts a toxic effect by itself or acts as a marker of an underlying disease resulting in an insufficient dietary intake of B vitamins. Previous studies have shown a very clear association between the MTHFR 677T allele and increased homocysteine levels (17,22). The fact that there is no relationship between this allele and cognitive decline or mortality in our study weakens the theory that homocysteine plays an independent role in aging. It seems much more likely that hyperhomocysteinemia is a consequence of age-related diseases than a contributory cause. A recent study in octogenarians showed a significant cross-sectional association between homocysteine and cognitive performance but no association between homocysteine and cognitive decline, supporting the hypothesis of hyperhomocysteinemia as a consequence of the cognitive decline, possibly caused by a change in dietary intake (13). However, the lack of association could also be explained by a decreasing effect of hyperhomocysteinemia on cognitive function with age, as suggested by a previous study in centenarians (32).

Increased homocysteine has been related to both cardiovascular and all-cause mortality in several studies (5,9,33). However, two recent studies evaluated the efficacy of homocysteine-lowering treatment with B vitamins for secondary prevention in patients, who had had vascular disease mainly as myocardial infarction (34,35). The studies showed that supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease. Increased homocysteine is related to smoking status, renal dysfunction, elevated blood pressure, and other cardiovascular risk factors, and homocysteine level is higher in people with atherosclerosis than in people without (16). Therefore, homocysteine could be a marker, and not a cause, of vascular disease. As a consequence, the link between the genetic factors influencing homocysteine levels and cognitive functioning could be absent, if indeed, the increased homocysteine levels only reflect the environmental factors resulting in atherosclerosis.

A recent meta-analysis found a graded increase in ischemic stroke risk with increasing MTHFR 677T allele dose, suggesting an influence of this polymorphism as a genetic stroke risk factor (36). However, we observed no significant association between the MTHFR and MTR genotypes and mortality but, as shown in Table 3, there is (as expected) a highly significant relationship between mortality, MMSE score, and gender. It is well known that the MMSE score declines with age in the oldest-old (37). This decline is obvious in our study and is clearly related to mortality as shown in Figure 1 and the survival statistics (Table 3). Women had an overall lower mean MMSE score at intake than did men. However, Figure 1 shows that the mean MMSE score is associated with later nonparticipation due to death and that the gender-specific differences in mean MMSE score is not present in the group participating in all three waves. Although social group exerts a significant influence on cognitive functioning, social group had no impact on survival in our study.

We assessed the complete Danish 1905 Cohort in 1998 (2,25), when the participants were 92–93 years old. This nonagenarian population has a very high mortality; as only about 1 in 20 of these survivors to age 92–93 will celebrate a 100 year birthday. The result is an extremely high rate of loss to follow-up. The question is, of course, whether the missing observations are missing not at random, but due to a higher risk of cognitive impairment in a specific genotype and, as a consequence, a higher mortality associated with that particular genotype. However, the resulting higher mortality would be seen in the survival analyses as it should be possible to detect even a small mortality difference in this large nonagenarian population. Furthermore, there are no difference in genotype distribution between the entire population and the group participating in all three waves; this indicates that death and nonparticipation is not genotype dependent. The fact that there is no association between genotype and cognitive function at intake or cognitive decline over 5 years, in combination with no significant impact on survival, makes it very unlikely that the two tested SNPs have an impact on cognitive functioning.

Increased plasma homocysteine has in several previous studies been associated with decreased cognitive functioning among the oldest-old. Despite the biological plausibility of an association between MTHFR and MTR genotypes, cognitive functioning, and survival, our data fail to confirm any association in this large study of nonagenarians.


   Acknowledgments
Top
 Abstract
 Participants and Methods
 Results
 Discussion
 References
 
This work was supported by National Institute on Aging Research Grant NIA-PO1-AG08761 and by The Danish National Research Foundation.


   Footnotes
Top
 Abstract
 Participants and Methods
 Results
 Discussion
 References
 
Decision Editor: Luigi Ferrucci, MD, PhD

Received December 16, 2005

Accepted May 31, 2006


   References
Top
 Abstract
 Participants and Methods
 Results
 Discussion
 References
 

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