Introduction
As life expectancy increases, a rapidly increasing number of people worldwide are affected by degenerative brain disorders (Mattson et al., 2002). It is vital to identify factors that influence neurodegeneration to promote successful brain aging through genetic (germline gene therapy) and environmental (dietary and behavioral) modifications.
Several new factors have recently been discovered that promote or resist brain atrophy in the elderly. Among those that could in principle be influenced by pharmaceutical or even dietary interventions are factors in the folate/homocysteine pathway (Smith et al., 2010). Homocysteine is an amino acid measurable in the blood. Genetic variations explain 45–60% of the variance in plasma homocysteine levels in normal adults (Bathum et al., 2007; Siva et al., 2007).
A commonly carried genetic variant – a single nucleotide polymorphism (SNP) (C677T locus; rs1801133) in the well-known candidate gene methylenenetetrahydrofolate reductase (MTHFR) on chromosome 1 – explains a fair proportion (24–53%) of this genetic variance (Bathum et al., 2007). The C677T change in the MTHFR gene replaces cytosine with thymine at base position 677. Carriers of the T allele have a less active MTHFR enzyme and higher homocysteine levels, especially when their folate levels are low. This has been consistently shown in several genome-wide association studies (Hazra et al., 2009; Lange et al., 2010; Mälarstig et al., 2009; Pare et al., 2009; Raz et al., 2011; Tanaka et al., 2009). ...
This risk variant is widely prevalent in the United States: 40% and 11% of the non-Hispanic white population carry one or two risk alleles, respectively (Yu et al., 2010); the minor allele frequency is reported to be 31% in Western and Central Europeans (Altshuler et al., 2010).
Homocysteine is toxic to neurons via direct DNA damage and excitotoxicity, inducing apoptosis (Sachdev, 2005). High homocysteine levels have also been associated with brain atrophy in the elderly. Recently, we have shown that higher plasma homocysteine levels are associated with regional brain volume deficits in elderly Caucasian people, more specifically in people with mild cognitive impairment (MCI) (Rajagopalan et al., 2011).
If homocysteine is associated with brain atrophy in elderly people with mild cognitive impairment, then carriers of the MTHFR C677T risk polymorphism may show detectable differences in brain structure on MRI. By showing that brain structure is affected not just by homocysteine levels, but also by a commonly carried genetic variant that in turn elevates plasma homocysteine levels, a causal pathway to brain atrophy could begin to be elucidated — revealing brain systems affected, and the extent of their deficits in risk variant carriers (Fig. 1)
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Folate is essential for the stability and synthesis of myelin basic protein, which, in turn, is essential for white matter structure in the central nervous system. It acts as a coenzyme for a large number of metabolic reactions in the body and affects brain structure independent of plasma homocysteine levels. Also, the effects MTHFR variant on plasma homocysteine levels are pronounced when serum folate levels are low. Therefore, we adjusted for folate in the MTHFR SNP associations with brain structure in the CHS study but found that it did not affect the associations. In the ADNI study – unlike the CHS – folate levels were not measured in the subjects; so we could not test for MTHFR associations with brain structure, independent of folate levels in ADNI subjects. Folate supplementation is known to improve cognitive performance in the elderly with dementia and elevated plasma homocysteine (Nilsson et al., 2001). We were unable to look into folate supplements as we did not have the necessary data in this imaged cohort.
When we adjusted for homocysteine levels in ADNI and CHS, the correlations for the MTHFR C677T risk allele with brain volumes weakened, suggesting that the MTHFR effect on brain structure may in part be due to homocysteine elevation induced by the risk allele. The MTHFR risk allele may also directly affect brain structure independent of the homocysteine pathway. The MTHFR risk allele that is known to increase homocysteine levels has been shown, albeit inconsistently, to be associated with AD (Anello et al., 2004; Brunelli et al., 2001; Mansoori et al., 2011; Prince et al., 2001; Wang et al., 2005), vascular dementia (Chapman et al., 1998; Pollak et al., 2000), silent brain infarcts (Kohara et al., 2003) and white matter hyperintensities (Hong et al., 2009; Kohara et al., 2003). This, by itself, may increase the MTHFR variant associated risk for brain atrophy through various mechanisms including plaques and tangles (Vermeer et al., 2007), in addition to increased homocysteine levels.
Our finding of the MTHFR gene variant associations with brain atrophy may have implications for randomized controlled trials of medications aiming to lower homocysteine levels to resist brain degeneration. Some clinical trials target the folate pathway specifically, and advocate taking high doses of B vitamins as a preventative measure against further brain atrophy (Smith et al., 2010) and cognitive decline (Jager et al., 2011) in subjects with mild cognitive impairment. In such trials, and in epidemiological studies, it may help to genotype at this MTHFR SNP, as these genotypes may influence homocysteine levels and the observed pattern of atrophy. Further cross-sectional and prospective studies will be helpful in replicating these findings.
Our study was carried out in a large well-characterized cohort (ADNI n = 359; CHS n = 51) with high-quality standardized brain MRI, and well-validated computational methods to map patterns and rates of brain atrophy at a local level. We found significant associations of the MTHFR SNP with brain volumes in the subjects diagnosed with MCI in both ADNI and CHS studies, even though the replication sample was relatively small (n = 51).
The minor allele frequency for the MTHFR SNP varies moderately across different populations worldwide, and is reported to be 31% in Western and Central Europeans, 33% in US Chinese, 16% in US Gujarati Indians, 41% in US Mexicans, and 12% in African Americans (Altshuler et al., 2010). The subjects analyzed in the study were of Caucasian origin in both the cohorts to avoid spurious results due to population stratification (Lander and Schork, 1994). As a result, care must be exercised in generalizing our findings to ethnic groups with different allele frequencies and possibly different environmental influences.
Homocysteine levels in the CSF and plasma are highly correlated (r = 0.85) (Selley et al., 2002) but it is difficult to ascertain whether plasma homocysteine and folate levels correlate between blood and cerebrospinal fluid, especially when their values are not very high, as in the subjects studied here. Therefore in addition to elevated homocysteine, several other mechanisms such as dietary methionine intake, toxic habits, and pyridoxal-phosphate levels may contribute towards the effect of the MTHFR SNP on brain structure. Unfortunately, these measures were not available to us in the current study.
Conclusions
These brain maps reveal that a commonly carried susceptibility allele for higher homocysteine is also associated with structural brain volume deficits and with accelerated rates of brain atrophy over time. As homocysteine is involved in this pathway and in the level of atrophy, the deficits may be resisted even in MTHFR gene risk allele carriers, at least in principle, via efforts to lower homocysteine levels. Healthy lifestyle changes such as increasing dietary folate and supplementation with B vitamins (Blaise et al., 2007; Smith et al., 2010) in carriers of the MTHFR risk variant may help slow the rate of atrophy, especially in elderly subjects with mild cognitive impairment.
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