Modern humans are rather unique among primates in that our brains appear to shrink as we age. Could that shrinkage have something to with our diet or lifestyle? Some of the more intriguing evidence that diet could play a role points to B vitamins and the folate cycle. In the folate cycle, B vitamins help the proteins we eat metabolize and modulate into all sorts of building blocks for all sorts of things we need in the body, such as neurotransmitters (like serotonin) and DNA.

In order to understand the evidence linking B vitamins to brain shrinkage (or atrophy), we have to look more closely at an amino acid called homocysteine. (1) Homocysteine is the bad boy of the folate cycle—always hanging out when everyone wants him to be recycled and go home. Homocysteine is created in the folate cycle but when nutritional states are optimal, and it is reused continuously. If you don't have optimal nutrition or functioning, higher than normal levels of homocysteine are released into the system. Homocysteine itself is likely biologically active, possibly cleaving the disulfide bridges of the elastic proteins, leaving your arteries and cartilage all crispy and brittle.  High homocysteine occurs in all sorts of states, including metabolic syndrome and even bipolar disorder, but it is most reliably linked to high blood pressure and vascular disease.

There is evidence to implicate homocysteine in increased oxidative stress, DNA damage, the triggering of apoptosis (cell suicide) and excitotoxicity (when nerve cells are damaged by too much activation), all important mechanisms in the process of brain atrophy.  The good news is, high homocysteine is readily reversed by supplementation with B vitamins. So if homocysteine causes brain shrinkage, could B vitamin supplementation protect us from it, possibly helping to prevent a variety of neurodegenerative disorders?

Let's break it down further. Homocysteine, vitamin B12, and folate are all vital components of the folate cycle. Deficiencies in those last two vitamins are clearly related to nerve damage in everyone and neural tube defects in newborns.  Deficiencies in either of these vitamins will lead to an increase in homocysteine, which is also apparently directly neurotoxic. The brain might be particularly vulnerable to higher levels of homocysteine because it lacks two major metabolic pathways for eliminating it (biochemistry nerds, hold on to your hats), remethylation, and transsulfuration.

All right.  That is theory, and lots of it.  What about the observational evidence?  Well, a number of cross-sectional studies have examined a relationship between too much homocysteine and brain atrophy.  In an Australian study of stroke patients, high homocysteine was related to increased brain atrophy, and the OPTIMA and Rotterdam studies replicated this finding in healthy elderly folks. Other observational studies have shown a correlation between higher homocysteine level and Alzheimer's disease, to the point where homocysteine levels seemed to be able to predict the speed of progression of the disease.

If we look at specific cognitive impairment trials, higher homocysteine levels have been shown to correlate with poorer performance on a number of cognitive tests such as story recall, spacial coping, etc.  In fact, homocysteine levels accounted for "7-8% of the variance in late-life cognitive ability."

In a prospective observational study (the Framingham heart study), higher homocysteine at baseline was related to an increased risk of developing Alzheimer's later on.  Several other smaller studies have repeated this finding.

Moving onto trials of B vitamins to lower homocysteine levels.  Folic acid supplementation can lower homocysteine by 25 percent, B12 by a further 7 percent.  Betaine is somewhat less effective.  These B vitamins have been used in experiments treating mild cognitive impairment and dementia.  In small, open-label trials, B vitamin supplementation (typically folate and B12) have been helpful in some tests of cognitive impairment and homocysteine levels. In 2010, this freely available study at PLOSone was published:  Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in  Mild Cognitive Impairment: A Randomized Controlled Trial.

Sounds cool, right?  Well, turns out the first author of the paper has a patent for a folate or B vitamin something-or-other in the treatment of Alzheimer's disease so keep that bias in mind, but the findings are still interesting.  One hundred sixty-eight folks with mild cognitive impairment were randomized to placebo or B vitamin supplementation (0.8 mg/d folic acid, 0.5mg/d vitamin B12, and 20 mg/d vitamin B6).  Both groups of people underwent baseline and serial follow up MRIs and cognitive testing.

In the end, the B vitamin supplementation seemed to slow the brain atrophy compared to the control group.  The treatment response was related to baseline homocysteine levels - the rate of atrophy in patients with a homocysteine level at baseline of >13 micromol/L was 53 percent lower in the active treatment group than in placebo.  A faster rate of atrophy was associated with lower cognitive testing scores.

So, pretty interesting.  And certainly treating our elders with B vitamin supplementation seems to have few downsides.  A lifetime of eating meat, leafy greens, organ meats and other food items rich in B vitamins (such as beans) might leave us well-served in that regard.

Thanks to Steve Parker, M.D. for pointing me to the B vitamin study.

Image Credit 

Copyright Emily Deans, M.D.


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