Sunday, October 31, 2010

B12, homocysteine and Alzheimer's

For this post I'm reviewing a paper from Neurology, October 2010, "Homocysteine and holotranscobalamin and the risk of Alzheimer's disease" along with the accompanying editorial, "Beauty and the beast: B12, homocysteine, and the brain: A bemusing saga!" (Neurologists don't have much time for poetry, I'm guessing.)(Dear neurologists and cardiologists, sorry for making fun of you all the time.)(As if a neurologist or cardiologist would bother to read this blog).(There I go again.)

So what's the scoop? We know the brain needs B12. Why? B12 is a cofactor in all sorts of enzymatic reactions to make neurotransmitters. Without neurotransmitters, the brain is left high and dry. Rather like a rock band without groupies or a fan club. Homocysteine is a part of the B vitamin processing shenanigans, and high levels homocysteine tend to indicate low levels of B12 and folate. Past observational studies have more or less shown that people with high homocysteine have more heart attacks, strokes, and dementia, while people with low vitamin B12 seem to have more dementia, cognitive impairment, and an increased rate of brain atrophy. I say more or less, because some studies don't show a connection, but overall, the tendency is for B12 to be associated with a happy brain, and for homocysteine to be associated with an unhappy brain. This tendency makes biological sense, so we can nod our heads a little in consideration.

(Important note - the organ meat eating "dietary pattern" that was associated with Alzheimer's disease in this study was especially high in B12! Weird, huh? As in totally doesn't make any biologic sense? Chris Masterjohn covers the silliness of dietary pattern studies in this wonderful post. I have a number of posts on certain dietary patterns and mental health disorders - I post on them because they are pretty much the only studies of diet and mental health we have, but I hope everyone understands the limitations of these studies. As in, they are extremely limited, incredibly vulnerable to data mining, and observational in nature. We can't make too many conclusions from the studies, though they may offer some ideas for some future hypotheses.)

Here's probably the most interesting thing about this study ("homocysteine and holotranscobalamin and the blah blah") - instead of measuring straight up serum B12, they measure the biologically active fraction, holotranscobalamin - otherwise known as holoB12. They suggest that holoB12 is the best lab test to measure B12 deficiency, which is news to me. And since I test B12 all the time, that's useful information. What is little known to psychiatrists and primary care docs is that B12 levels that are in the low range of normal can be associated with psychiatric symptoms, such as depression. Most lab tests of B12 will suggest 200 to 1200 is normal. 200-400 is probably too low, however, and most people I test are in that range unless they are dedicated liver eaters (rare) or multivitamin takers. The latest practice guidelines for prescribing antidepressants suggests that antidepressants won't work as well until the B12 level is higher than 400. Who knows what holoB12 would show?

Back to the study! 271 dementia-free Finnish participants in the CAIDE study were examined in 1998 and 2005-2006. Serum blood levels of holoB12, homocysteine, and folate were available in 1998 along with MMSE scores, and at the follow-up several years later, individuals were examined for dementia with the MMSE (a short, rather crappy test for dementia), and those who scored badly or whose scores decreased significantly from 1998 were more closely examined with much better neuropsychologic tests, brain imaging, CSF analysis, and blood tests. This is yet another observational study, and a basic one, though at least no waters are muddied with "dietary pattern" adjustments.

Results! 17 of the 271 folks ended up with Alzheimer's. People who developed Alzheimer's were older, had a lower BMI, and higher frequency of the ApoE4 allele. They also had lower holoB12 and higher homocysteine compared to subjects without dementia. Folks with higher homocysteine tended to be older, male, and had lower holoB12. Folate (another B vitamin whose deficiency is associated with nerve problems, depression, and dementia) didn't seem to have much to do with anything. My own clinical experience with folate is that no one seems to be low, and supplementing with special bioavailable folate doesn't seem to help much. The deplin folks should have been powdering grass fed beef liver and putting it into pills, I suppose.

Discussion! High homocysteine and low holoB12 in 1998 showed increasing risk for dementia many years later, independent of other known risk factors, such as age or ApoE4 status. In the Framingham study and some other long term population observational studies also showed high homocysteine to be a risk factor for later Alzheimer's, dementia, and cognitive impairment.

What could be going on then, biologically? High homocysteine levels are associated with low B12, endothelial dysfunction, atherosclerosis, and poor nitric oxide activity. Elevated homocysteine might be a part of beta amyloid generation, cause DNA damage, and impair DNA repair. Oh - here's something interesting - homocysteine can become homocysteic acid, which is highly neurotoxic and an NMDA receptor activator!

Some more interesting biochem - remember SAMe? Well, vitamin B12 is desperately needed to add methyl groups to homocysteine to make methionine, and then SAM. Lack of SAM is linked to nerve damage, depression, cognitive decline, and dementia.

Well! A few years ago, it was noticed that low folate levels was associated with high homocysteine and heart disease. A number of studies and clinical trials were attempted, and were basically a total bust. Turns out, maybe it wasn't folate after all, but B12 instead. Which makes more sense, seeing as how it is relatively easy to be fine in folate levels on a SAD, but rather difficult to be replete in B12. We're still waiting for the clinical (randomized controlled) trials of B12. Maybe the answers of the homocysteine mystery will be found there?

Music link for the week - La Befana, Respighi, Fountains of Rome.  Another unbelievable recording. Happy Halloween!


  1. all i know (i.e have read) is that lowering homocysteine with folate AND B12 doesn't change the risk for heart disease at all. so i think the question for B12 is already answered there. but it could be different with regard to the brain of course. apropos depression - did you know the following:
    "Activated vitamin D in the adrenal gland regulates tyrosine hydroxylase, the rate limiting enzyme necessary for the production of dopamine, epinephrine and norepinephrine. Low vitamin D may contribute to chronic fatigue and depression. Seasonal Affective Disorder has been treated successfully with vitamin D. In a recent study covering 30 days of treatment comparing Vitamin D and 2 hour daily use of 'light boxes', ***depression completely resolved in the D group***, but not in the light box group."

    did you ever actually have a patient with depression walking into your practice that had an optimal (say, >=50ng) D level? meaning, could id be, that D deficiency is actually (statistically) the MAIN cause of depression? i'm asking because i just started megadosing D3 after my more conservative dosing regime (i.e. up to 10kIU) failed to raise my level over 24ng for over half a year. now, a few days ago i tried 50'000IU out of curiosity, and BOOM!! my brains suddenly wakes up and almost goes into overdrive! now, after tinkering around with different dosages, i found out that the neuro-boost effect starts at around 15kIU, is "optimal" at around 20kIU, and even feels a bit too strong from 25kIU and above. at 20kIU, it feels pretty much like 150mg wellbutrin, which i also tried out of curiosity just recently.
    Q: have you ever tried treating a depressed patient with high(er) doses of D, like 20kIU or even 50kIU? could it be that this is actually all what is needed on the biological level, provided that all other nutritional deficiencies can be ruled out? i mean, there is certainly no known prozac or wellbutrin deficiency in humans right? but the same is not true for D! could it be that most depressed patients actually would need a few month of supra-physiological levels of D to make up for the decades of D deficiency the were walking around all the time to re-balance their neuro-transmitter levels? i mean, it seems to do exactly that with my brain (for now at least). what are your experiences with D supplementation and neurotransmitter levels?

  2. Qualia - definitely no known Prozac or wellbutrin deficiencies. However, I've repleted several patients to the 50s level of vitamin D3 with only subtle results. I did it day by day with more physiologic doses, however, not 50,000 or 20,000 - more like 4k or 2k per day. I know my posts are pro antidepressant - however the basic science research seems to be quite pro- antidepressants. I'm guessing SSRIs are perfect for rats.

  3. Emily, I would love here your take on the whole natural vs synthetic B-Vitamins debate. Thing's such as Sulbutiamine etc.

    Apologies if you have answered this before!

  4. Paleo Rob - I will look into that. I haven't answered it before!

  5. Hi
    This is likely the wrong specific post for this, but I'd love your thoughts on this article tying HSV1 to Alzheimer's disease:

    The authors tie the risk factors to ApoE4, inflammation, etc.

    As a bit a background, I feel stalker-ish but I've followed your blog(s) since you were once doing body for life, short fiction, mommy blogging, etc. I'm a PhD in biochem but also passionate about performance nutrition and wellness in general. I've personally learned through trial and error (aka elimination dieting) that casein and gluten are terrible for my body, and love what you are doing with this specific blog. Awesome stuff. Please keep it coming.

  6. Paleo Rob - just reminding myself here that Maurizio Fava did a review of b vitamins and the different formulations in the journal of clinical psychiatry in 2009 - I'm going to look at that and get back to you (either here or in another post).

    Cathy - thanks for the support! I think the alzheimer's/infection idea is very compelling, and I do plan to do a post on it, though I have pulled papers on some other topics to cover first. Thanks for the link!

  7. What are your thoughts on the use of serum MMA to detect B-12 deficiency. I almost always see MMA well WNL even with B-12 in the 200's in my patients. Also, my experience with vitamin D mirrors yours

  8. PR - literature seems pretty consistent with respect to MMA being positively correlated with homocysteine and inversely correlated with serum B12 - I've not checked that myself. I've had PCPs ignore my low B12s and recommend against supplementing because there were no hematologic findings, though. Very annoying.