Douaud G, Refsum H, de Jager CA, et al. Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci. 2013;110(23):9523-9528.
A randomized, placebo-controlled study. This 2-year study used daily folic acid (800 mcg), vitamin B6 (20 mg), and vitamin B12 (500 mcg) versus placebo in elderly subjects with mild cognitive impairment. Identification of the Apolipoprotein e allele epsilon 4 (APOE ε4), a known risk factor for Alzheimer’s, was done for most, but not all, individuals in the study. Measures of plasma homocysteine, vitamin B6, vitamin B12, folate, and creatinine were assessed along with cognitive function, and gray matter volume.
This study evaluated 156 subjects with a mean age of 76. Seventy-six received placebo and 80 received the B-vitamin complex. The placebo group consisted of 25 out of 51 (49%) who tested positive for the APOE ε4 variant allele while the B vitamins group consisted of 20 out of 60 (33%). At baseline, the 2 groups did not differ in gray matter volume. Participants were further divided based on whether their homocysteine levels were over or under the median level (11.06 µmol/L). Each group consisted of placebo and intervention of the B-vitamin complex.
The primary outcome measure was gray matter volume determined by MRI scans. Secondary outcome measures were plasma levels of homocysteine, B12, B6, and folate.
Comparing placebo versus the B-vitamin complex intervention, the group receiving the B-vitamin complex demonstrated significant reduction of overall brain atrophy.
When looking at just the placebo group, those with homocysteine levels above the median had greater gray matter atrophy than those with homocysteine levels below the median.
The group with homocysteine levels above the median that received the B-vitamin complex had the most significant reduction in gray matter atrophy—from 5.4% down to 0.6%. The group with homocysteine levels below the median that received the B-vitamin complex did not show significant reduction of gray matter.
This study points out the importance of maintaining healthy levels of homocysteine to prevent reduction in gray matter and support healthy cognition. That said, there are several issues with the study that must be pointed out.
Alzheimer’s is a serious diagnosis and warrants rigorous intervention. While paying attention to elevated homocysteine, APOE alleles, and vitamin B-deficiencies may provide benefit, we should look for and treat a greater range of factors.
Not all of the study participants were tested for the APOE allele. “The APOE ε4 allele is a risk factor for late-life pathological changes that is also associated with anatomical and functional brain changes in middle-aged and elderly healthy subjects.”1 Of the participants tested, APOE ε4 alleles were distributed unevenly between the placebo and the experimental groups. In the placebo group, 51 of the 76 participants were tested and 25 (49%) had the APOE allele. In comparison, 60 of the 80 members of the experimental group were tested and 20 (33%) possessed the allele. The study authors used Bayesian network analysis to counter this possible confounding effect.
Simply prescribing 3 B vitamins for a seriously debilitating condition like Alzheimer's, while of potential benefit, is inadequate.
The study does not specify which forms of B vitamins were used for treatment. The vitamin B12 was described simply as ‘vitamin B12,’ so the specific form is unknown. Most of us would think that varying forms of B12 may have different physiological impacts. Folic acid was used rather than methylfolate, but methylfolate, as it is the primary form of folate found in the CNS, may have been a better choice as it might have a greater impact on supporting healthy cognition.2 Using methylfolate may have been of greater benefit as it might have compensated for those individuals with the MTHFR C677T variant that is associated with Alzheimer’s disease risk.2
MTRR 66G variant contributes to late-onset Alzheimer’s disease (LOAD).3 This study did not evaluate for the MTRR 66G. Normal plasma levels of vitamin B12 were found for all study participants. Other assessment tools that could have been employed include methylmalonic acid WBC, MCH, MCV, RDW, or serum ferritin. Thus, it is not known if various anemias were present in any of the study participants. Elevated RDW and anemia are both known risk factors for dementia.4
Rather than simply testing homocysteine, a more appropriate way to evaluate patients with cognitive decline would be to measure methylation status directly. Evaluating the ratio of s-adenosylmethionine (SAM) and its metabolite, s-adenosylhomocysteine (SAH) is the current standard for doing so.
Adequate levels of SAM and healthy levels of SAH are needed to prevent inhibition of other critical DNA methyltransferase enzymes such as DNMT1. Increased expression of amyloid-β precursor protein occurs when the DNMT1 enzyme is demethylated. Demethylation of DNMT1 occurs during times of elevated SAH and diminished SAM. Amyloid-β plaques are a hallmark finding in those with Alzheimer’s disease. As hypomethylation continues to occur, DNMT1 further downregulates and causes the protective coating on DNA, histones, to unwind. As the DNA histones fall off and expose the DNA, increased transcription occurs that further increases amyloid-β plaques.5
All of us on the front line of patient care have the responsibility to identify the causes of our patient’s condition, remove those causes if possible, and help restore function. Simply prescribing 3 B vitamins for a seriously debilitating condition like Alzheimer’s, while of potential benefit, is inadequate. Though the results in this study are impressive, it would be more appropriate to take a thorough history and test for genetic variants, methylation pathway imbalances, oxidative stress, and cell membrane health. Then with this information, we should work to restore our patients by employing lifestyle and dietary changes, as well as the most effective forms of nutrients available.
- Filippini N, Macintosh BJ, Hough MG, et al. Distinct patterns of brain activity in young carriers of the APOE-epsilon4allele. Proc Natl Acad Sci. 2009;106(17):7209-7214.
- Michelakos T, Kousoulis AA, Katsiardanis K, et al. Serum folate and B12 levels in association with cognitive impairment among seniors. J Aging Health. 2013;25(4):589-616.
- Coppede F, Tannorella P, Pezzini I, et al. Folate, homocysteine, vitamin B12, and polymorphisms of genes participating in one-carbon metabolism in late-onset Alzheimer's disease patients and healthy controls. Antioxid Redox Signal. 2012; 17(2):195-204.