It’s been over a year since I posted here. There are lots of reasons why. In that time, just to touch on the high points, my mother died and I suffered a major injury to my right arm which makes it hard for me to type and write and such. There has been so much happening in this space about which I really WANTED to write! The whole brouhaha with 23andMe and the FDA was a big one. There have been a number of interesting research articles that have come out. I did a presentation about my condition and meant to share the slides here. I may still, someday, write about these things.
For today, I want to talk about the research connecting genetic changes to the MTHFR gene to Alzheimer’s, Mild Cognitive Impairment (MCI), Vascular Cognitive Impairment (VCI), and related cognitive challenges. Because of my ongoing challenges with typing, I’m going to keep this simple, by selecting examples of the research and giving very brief snippets of the key findings. In other words, what’s most important.
The reason why I want to do this is because a friend of mine was recently diagnosed with one of these conditions, and so many doctors are not aware of this connection and don’t look for it. I’ve heard that from a number of places, but have a particular story that really rammed it home for me. As a medical librarian who works with systematic reviews, I’m on a number of medical and library email lists with various medical experts in different disciplines. On one of those lists, a clinician posted a question about this question. He is a recognized expert in his field and an expert in seeking and finding quality medical information. The family of one of his patients had approached him. Their mother has Alzheimer’s and they were wondering about giving her methylfolate supplements to help slow or arrest her memory loss. He wasn’t convinced, and was reluctant to support the family with this request. But he found enough evidence in support of the idea that he wanted to ask other professionals about the idea, and whether any of them had strong feelings about this. I sent him my search strategy and a few selected citations, and hoped for the best. I wondered, though, if someone as expert as he is was unaware of this, and reluctant to go along with a family’s request, what hope do others have with doctors who may very well not even ask the questions he was asking.
That was someone far away, in another country. I have no idea what happened. Now it is my friend, and I’m not close enough to talk with her clinicians. I’m hoping that someone will show this to her doctor, and if that doesn’t happen, maybe it will help someone else.
For the record, this is also a topic I follow because of personal concerns. When I was 12 I was briefly a significant part of my grandmother’s caregiving team. I was told at the time that she had Alzheimer’s, and it frankly terrified me. Years later, following brain damage from longterm carbon monoxide poisoning (another story for another day), I not only had amnesia but seemed to be developing mild cognitive impairment. It took me years to admit this to my doctor, and then brought it up at every appointment for the next few years. I won’t bore you with what didn’t work, but when I serendipitously discovered the MTHFR deficiency and began taking methylfolate, all my memory problems disappeared. Poof! Just like that. It was pretty amazing, and they haven’t come back. (Well, as long as I don’t get glutened.) Then, in the final part of her life my mother had cognitive decline. We don’t know her MTHFR status because we couldn’t get her genome tested, but we do know from testing other family members that she had at least one copy of the A1298c polymorphism. So, yes, I have a personal bias regarding this. That’s an excellent reason for me to stick to the evidence and what it says instead of trying to interpret it for you.
LOOKING AT THE RESEARCH
There are several MTHFR variations which are considered potential problems. The big ones are C677t and A1298c, with newer and less well understood, the MTHFR 03 P39P. The SNPs (snips) for these are:
* MTHFR C677t = rs1801133
* MTHFR A1298c = rs1801131
* MTHFR 03 P39P = rs2066470
Each of these is associated with different health impacts. A study that shows that one of them does something (or does not) says absolutely nothing about the other variants. There isn’t enough research yet to look at all of them together across the board. For many of the MTHFR variations, one common association is for increases in homocysteine (hyperhomocysteinemia), which in and of itself causes much damage in the body.
So, to start off, here is the Pubmed search strategy I’m using to try to get to just high quality research on this topic.
(mthfr OR methylfolate OR L-methylfolate OR Methylenetetrahydrofolate OR 5-mthf OR l-5-mthf) (“alzheimer disease”[MeSH Terms] OR “Mild Cognitive Impairment”[MeSH Terms] OR “dementia, vascular”[MeSH Terms] OR “dementia”[MeSH Terms] OR “Cognition Disorders”[MeSH Terms] OR “memory disorders”[MeSH Terms] OR “amnesia”[MeSH Terms])
Today, that results in 121 citations. Since this topic actually has fairly deep roots in the literature, going back to at least the early 1990s, I’ll be selective and focus on newer articles. To be even more selective, I am limiting this to systematic reviews and meta-analyses, the very top quality evidence available, and only the most recent of those available in English. Systematic reviews and meta-analyses distill the best evidence available into recommendations for clinical practice. In other words, they look through the whole puzzle and say, “This is what doctors need to know, and what they should consider doing.” After that, I may add just a couple very new research studies that would not have been included in the reviews.
For me, I will say that while some of these show a strong connection and others only a weak connection, there aren’t any that show no connection or the opposite. The gathering of these large aggregated studies together confirms a solid connection in some populations and is suggestive that may not have enough data to know yet about other populations. If it was me or my loved one, I’d wonder if it is worth at least doing a test and considering possible low levels of supplementation with methylfolate as a low-cost, low-risk intervention, and then seeing how the patient responds.
SYSTEMATIC REVIEWS AND META-ANALYSES
Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007 Jan;39(1):17-23.
In addition to identifying the epsilon4 allele of APOE and related effects, we pinpointed over a dozen potential Alzheimer disease susceptibility genes (ACE, CHRNB2, CST3, ESR1, GAPDHS, IDE, MTHFR, NCSTN, PRNP, PSEN1, TF, TFAM and TNF) with statistically significant allelic summary odds ratios (ranging from 1.11-1.38 for risk alleles and 0.92-0.67 for protective alleles).
Laumet G, Chouraki V, Grenier-Boley B, Legry V, Heath S, Zelenika D, Fievet N, Hannequin D, Delepine M, Pasquier F, Hanon O, Brice A, Epelbaum J, Berr C, Dartigues JF, Tzourio C, Campion D, Lathrop M, Bertram L, Amouyel P, Lambert JC. Systematic analysis of candidate genes for Alzheimer’s disease in a French, genome-wide association study. J Alzheimers Dis. 2010;20(4):1181-8. doi: 10.3233/JAD-2010-100126.
We selected twenty genes from the “Top Results” list on the AlzGene database website and assessed their association with risk of developing Alzheimer’s disease (AD) in a large, genome-wide association study (using 526 SNPs from 2,032 AD cases and 5,328 controls) performed in France. The APOE, CLU, PICALM, and CR1 loci were excluded, since they had already been extensively analyzed. Ten genes/loci (TFAM, SORL1, CHRNB2, SORCS1, DAPK1, MTHFR, GWA 14q32.13, BDNF, NEDD9, and CH25H) showed weak nominal association with AD risk, in line with previous studies. In the remaining ten genes/loci (TNK1, ACE, CST3, IL1B, hCG2039140, PRNP, GAB2, LOC651924, IL1A, and TF), no single nucleotide polymorphisms were associated in our dataset. Of the genes showing nominal association in our cohorts, TFAM and CHRNB2 appear particularly interesting and warrant further genetic and functional follow-up analyses.
Liu H, Yang M, Li GM, Qiu Y, Zheng J, Du X, Wang JL, Liu RW. The MTHFR C677T polymorphism contributes to an increased risk for vascular dementia: a meta-analysis. J Neurol Sci. 2010 Jul 15;294(1-2):74-80. doi: 10.1016/j.jns.2010.04.001. Epub 2010 May 2.
RESULTS: A total of 11 studies, comprising 672 cases and 1038 controls, were included worldwide. Publication bias was not observed. This meta-analysis demonstrated that the MTHFR T allele or TT genotype had an increased risk for VaD in general populations (OR, 95%CI: 1.27, 1.01-1.59; 1.41, 1.06-1.88, respectively), and a significant association was found in allele contrast, recessive, and dominant model in Asian populations, but not in Caucasian populations.
CONCLUSION: The MTHFR C677T polymorphism (mainly TT genotype) is associated with developing VaD in general populations or Asian populations.
Zhang MY1, Miao L, Li YS, Hu GY. Meta-analysis of the methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to Alzheimer’s disease. Neurosci Res. 2010 Oct;68(2):142-50. doi: 10.1016/j.neures.2010.06.011. Epub 2010 Jun 30.
No clear consensus has been reached at the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and Alzheimer’s disease (AD) risk. Thus in this meta-analysis, a total of 19 case-control studies was assessed to evaluate the possible association. The data demonstrated that the frequency of T677 allele (T vs. C) was significantly associated with susceptibility to AD in all subjects (OR=1.15, 95% CI=1.06-1.26) and in East Asians (OR=1.22, 95% CI=1.08-1.39). … A subgroup analysis in the subjects without APOE epsilon4 alleles showed T677 allele significantly increased risk of AD in all subjects (OR=1.21, 95% CI: 1.04-1.42) and in East Asians (OR=1.28, 95% CI: 1.06-1.55). However, no association was found in Caucasians. In conclusion, this meta-analysis supports that MTHFR C677T polymorphism is capable of causing AD susceptibility in East Asians, not in Caucasians.
Hua Y1, Zhao H, Kong Y, Ye M. Association between the MTHFR gene and Alzheimer’s disease: a meta-analysis. Int J Neurosci. 2011 Aug;121(8):462-71. doi: 10.3109/00207454.2011.578778. Epub 2011 Jun 10.
RESULTS: This meta-analysis demonstrated that the MTHFR T allele or dominant model for T allele (CT + TT) had an increased risk for AD in combined populations (OR, 95% CI: 1.13, 1.05-1.21; 1.18, 1.07-1.31, respectively), and a significant association was found in allele contrast, recessive, and dominant model in Asian populations, but not in Caucasian populations.
CONCLUSION: The MTHFR C677T polymorphism is associated with AD in Asian populations, but not in Caucasians.
Dwyer R, Skrobot OA, Dwyer J, Munafo M, Kehoe PG. Using Alzgene-like approaches to investigate susceptibility genes for vascular cognitive impairment. J Alzheimers Dis. 2013 Jan 1;34(1):145-54. doi: 10.3233/JAD-121069.
Vascular cognitive impairment (VCI), including vascular dementia, is the second most common dementia after Alzheimer’s disease. Despite its prevalence, the genetic etiology of sporadic VCI is largely unknown. … Associations of increased risk for VCI were found for APOE ε4 (1.818 (95% CI = 1.611-2.053), p < 0.001; n = 3,554 cases, n = 12,277 controls) and MTHFR rs1801133 (1.323 (95% CI = 1.061-1.650) p = 0.013); n = 659 cases, n = 981 controls). There was marginal evidence of a protective effect for APOE ε2 (0.885 (95% CI = 0.783-0.999), p = 0.048; n = 3,320 cases, n = 10,786 controls). This systematic study of all published genetic association studies of sporadic VCI supports MTHFR and APOE as susceptibility genes for VCI.
Grarup N, Sulem P, Sandholt CH, Thorleifsson G, Ahluwalia TS, Steinthorsdottir V, Bjarnason H, Gudbjartsson DF, Magnusson OT, Sparsø T, Albrechtsen A, Kong A, Masson G, Tian G, Cao H, Nie C, Kristiansen K, Husemoen LL, Thuesen B, Li Y, Nielsen R, Linneberg A, Olafsson I, Eyjolfsson GI, Jørgensen T, Wang J, Hansen T, Thorsteinsdottir U, Stefánsson K, Pedersen O. Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets. PLoS Genet. 2013 Jun;9(6):e1003530. doi: 10.1371/journal.pgen.1003530. Epub 2013 Jun 6.
Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B(12) (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B(12) and folate measurements, respectively. We found six novel loci associating with serum B(12) (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B(12) and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimer’s disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B(12) or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations.
OTHER RECENT STUDIES
Mansouri L1, Fekih-Mrissa N, Klai S, Mansour M, Gritli N, Mrissa R. Association of methylenetetrahydrofolate reductase polymorphisms with susceptibility to Alzheimer’s disease. Clin Neurol Neurosurg. 2013 Sep;115(9):1693-6. doi: 10.1016/j.clineuro.2013.03.015. Epub 2013 May 6.
RESULT: Genetic analyses did not indicate a significant association between the MTHFR C677T mutation and AD (C/T: 63.15% versus 39%, p=0.087). However, the genotype prevalence of the missense variant MTHFR A1298C was significantly different between patients and controls (A/C: 55% versus 7%, p<10(-3)). Our data suggest an association between the MTHFR A1298C mutation and AD; however, the MTHFR C677T mutation did not contribute to susceptibility for AD.
CONCLUSION: The MTHFR A1298C polymorphism is a possible risk factor for Alzheimer's disease.
Farkas M1, Keskitalo S, Smith DE, Bain N, Semmler A, Ineichen B, Smulders Y, Blom H, Kulic L, Linnebank M. Hyperhomocysteinemia in Alzheimer’s disease: the hen and the egg? J Alzheimers Dis. 2013;33(4):1097-104. doi: 10.3233/JAD-2012-121378.
Hyperhomocysteinemia is associated with Alzheimer’s disease (AD). The causality of this association is controversial. … In conclusion, this data may argue that folate reduction and hyperhomocysteinemia may contribute to neurodegeneration and may also be triggered by neurodegenerative processes, i.e., represent both a cause and a consequence of neurodegeneration. Such a vicious cycle may be breakable by dietary or supplementation strategies increasing the availability of 5-MTHF.
Jin P1, Hou S, Ding B, Li D, Liu L, Li H, Li L, Zhao G, Shao Z, Liu X. Association between MTHFR gene polymorphisms, smoking, and the incidence of vascular dementia. Asia Pac J Public Health. 2013 Jul;25(4 Suppl):57S-63S. doi: 10.1177/1010539513492819. Epub 2013 Jul 15.
This study investigated the relationship between N5,N10-methylene tetrahydrofolic acid reductase (MTHFR) polymorphisms, smoking, and vascular dementia (VD). … The T allele frequency was significantly higher in the VD group than in the control group (P < .05). Among patients who smoked, the relative risk of VD in patients with the TT genotype and T allele was higher than in the control group (P < .05). Therefore, the smoking group with the T allele has the highest risk of VD, and synergy appears to exist between the MTHFR gene polymorphisms and smoking in susceptibility to VD.