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!