Methylation Status May Be a Modifiable Risk Factor for Dementia

Methylation, the movement of methyl (-CH3) groups from one molecule to another, is a critical step in many biochemical processes. Having adequate methyl groups to donate is a rate-limiting factor in these processes, and the methylation cycle is at the center of the methyl group marketplace. This cycle ultimately shuttles methyl groups back and forth between methionine, a methylated amino acid, and homocysteine, the non-methylated form. Along the way, several important vitamins and cofactors are involved, including B12, S-adenosylmethionine, and folate. Elevated homocysteine levels, indicating a lack of available methyl groups for donation, has been linked to cardiovascular disease risk,1 and dysfunction in methylation has also been linked to risk of several types of cancer.2 Now, a new study has associated methylation status with dementia risk.

For some time now, researchers have been questioning whether methylation status is associated with incident dementia and structural brain changes in older adults. A raised concentration of plasma total homocysteine (tHcy) reflects the status of three B vitamins (folate and vitamins B12 and B6), and researchers have speculated that the identification of these vitamins as a modifiable risk factor could provide a crucial approach to the treatment of cognitive decline and dementia.3,4 As well, the connection may prove integral for an accurate and timely diagnosis of the disease.5 Researchers across the board agree that an accurate and timely diagnosis of dementia is key for the optimal targeting of interventions.5

To this end, researchers published some promising results in JAMA Psychiatry. In a population-based longitudinal study, researchers studied the correlation of serum markers of methylation status and sulfur amino acids with risk for incident dementia, Alzheimer’s disease, and rate of total brain tissue volume loss over a six-year period.6 Their results found that the ratio of methionine to homocysteine may indeed be linked to dementia development and structural brain changes, indicating that a higher methionine to homocysteine ratio may reduce the risk for dementia in older adults.6 In other words, impairment of methylation status may be a modifiable risk factor for structural brain changes and incident dementia, and thus a potential target in preventive interventions.6

“Whereas several studies have reported an association between increased [serum total homocysteine] values and dementia or structural brain changes, only a few cross-sectional studies have investigated the associations between methylation status (ie, methionine to homocysteine ratio) and cognitive impairment or dementia with mixed results,” Dr. Hooshmand, from the Karolinska Institutet Aging Research Center, and colleagues wrote.6

In the cohort study of longitudinal data from 2,570 elderly individuals who were dementia free at baseline, a higher methionine to homocysteine ratio was observed in patients with better B12 or folate status and was associated with decreased risk of incident dementia and Alzheimer’s disease.6

The methionine to homocysteine ratio was higher in individuals who consumed vitamin supplements compared with those who did not, and increased per each quartile increase of vitamin B12 or folate.6 Higher values of the methionine to homocysteine ratio were significantly associated with lower risk of dementia and Alzheimer’s disease. As well, a higher methionine to homocysteine ratio was associated with a decreased rate of total brain tissue volume loss during the study period.6

A better methylation status, reflected by a higher methionine to homocysteine ratio, may be beneficial for the structure and functioning of the brain,” Hooshmand and colleagues6

“Because of the observational design of our study, a causal interpretation of our findings cannot be made … [However], high tHcy and low B12 and folate levels are surprisingly common conditions in older adults, and our results indicated a better methionine to homocysteine profile in participants with adequate B12 or folate values. If the association is found to be causal, supplementation with B vitamins may be effective for prevention of brain damage and dementia risk because of increased tHcy and impaired methylation reactions.”6

Vitamin B12 and folate are essential vitamins for the remethylation of homocysteine to methionine and the subsequent formation of S-adenosylmethionine, the primary methyl donor for many biochemical reactions involved in normal brain functions.6 When this process is disrupted, the serum tHcy may accumulate; this has been associated with several cerebrovascular and cardiovascular conditions. Elevated tHcy levels may further impair methylation status by converting to S-adenosyl homocysteine (SAH), an inhibitor of several methyl transferases.6

“The public health significance of raised tHcy in the elderly should not be underestimated, since it is easy, inexpensive, and safe to treat with B vitamins,” writes Dr. David Smith et al in a 2018 international consensus statement published in the Journal of Alzheimer’s Disease.7 In the study, researchers examined the question: “Is raised tHcy a direct cause of cognitive impairment or could elevated tHcy simply be a marker of causes like poor lifestyle, and/or inadequate B vitamin status?” Most prospective studies have found that raised tHcy remained associated with cognitive impairment even after adjusting for B vitamin status, consistent with tHcy being a risk factor for cognitive impairment independent of the B vitamins. In a 2013 trial, Bayesian analysis showed that lowering tHcy by B vitamin treatment mediated the slowing of regional brain atrophy, which, in turn, mediated the slowing of cognitive decline.7

The brain is particularly vulnerable to vitamin B12 deficiency, and suboptimal B12 status is common, occurring in 30-60% of the population, particularly in pregnant women and in less developed countries.3 Dementia is a major public health issue with rising prevalence rates, and many individuals remain undiagnosed.5 By 2050, for the first time in history, there will be fewer young people than older people.8 In 2018, more than 48 million people worldwide lived with dementia, and it is estimated that, owing to the lack of preventive therapeutics, there will be more than 130 million patients by 2050.9

Research suggests that most people currently living with dementia have not received a formal diagnosis.10 In high income countries, only 20-50% of dementia cases are recognized and documented in primary care. This ‘treatment gap’ is certainly much greater in low and middle income countries, with one study in India suggesting that 90% remain undiagnosed.10 Earlier diagnosis and early intervention are important mechanisms by which the treatment gap can be closed. Prevention, of course, is even better.

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  2. Hamidi T, Singh AK, Chen T. Genetic alterations of DNA methylation machinery in human diseases. Epigenomics. 2015;7(2):247-265. doi:2217/epi.14.80
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  6. Hooshmand B, Refsum H, Smith AD, et al. Association of methionine to homocysteine status with brain magnetic resonance imaging measures and risk of dementia. JAMA Psychiatry. Published online July 24, 2019. doi:1001/jamapsychiatry.2019.1694
  7. Smith AD, Refsum H, Bottiglieri T, et al. Homocysteine and dementia: an international consensus statement. J Alzheimers Dis. 2018;62(2):561-570. doi:3233/JAD-171042
  8. US Census Bureau. Older people projected to outnumber children for the first time in U.S. history. Published March 13, 2018. Revised September 6, 2018. Accessed August 5, 2019.
  9. Delgado-Morales R, Esteller M. Opening up the DNA methylome of dementia. Mol Psychiatry. 2017;22(4):485-496. doi:1038/mp.2016.242
  10. Alzheimer’s Disease International. Dementia statistics. Accessed August 5, 2019.