Fight Alzheimer's and Heart
Disease with B-Vitamins

Deficiencies of vitamin B12 and folic acid can
put your brain as well as your heart at risk

uppose you're an older person, and you're pretty sharp - all the lights are still on upstairs. Now suppose your neighbor down the street is the same as you in every respect but one: although he is, of course, a fine fellow, he's . . . well, perhaps a few of his bulbs are flickering. He certainly doesn't have dementia of any kind, but he wouldn't exactly ace a test of cognitive function: memory, learning ability, attention, focus, etc.

Suppose also that neither you nor your nice but woolly neighbor were taking any nutritional supplements that are effective in preventing dementia (see the sidebar "What Is Dementia?"). Got the picture? Now, guess which one of you is more likely to become afflicted with dementia as time goes on.

What Is Dementia?

In general, dementia is a progressive loss of memory accompanied by significant impairment in other areas of mental function or behavior. There are over 60 different causes of dementia, but the great majority of cases fall into just two categories: Alzheimer's disease and vascular dementia.

Alzheimer's is characterized by reduced levels of the neurotransmitter acetylcholine in certain parts of the brain, a substantial loss of neurons (brain cells), and the development of pathological changes in the brain called plaques and tangles. Whether these are causes or effects of Alzheimer's is not known. In any case, the true causes of Alzheimer's remain largely a mystery. A number of substances - notably galantamine and huperzine A - that can be found in some nutritional supplements have been found to be helpful for Alzheimer's.

Vascular dementia (dementia related to the brain's blood vessels) is better understood. Impairment of blood flow to the brain, or to certain parts of it, can damage the neurons by depriving them of adequate nutrients, such as oxygen and glucose. The principal cause of such impaired blood flow is atherosclerosis, but it can also be caused by hypertension and, of course, stroke. Among the substances found in nutritional supplements that are helpful for atherosclerosis, and thus vascular dementia, are policosanol, red yeast rice, and chelating agents such as EDTA.

SURPRISE!
The answer is . . . you! That startling conclusion popped out of an epidemiological study performed recently in Sweden.1 The objective of the study was not to evaluate cognitive function as a risk factor for dementia (that was more or less an afterthought), but rather to determine the extent to which low levels of vitamin B12 (cyanocobalamin) and folic acid (which is also a B-vitamin, but without a number) are a risk factor for dementia - Alzheimer’s disease in particular. As we will see below, they found that low levels of these vitamins are a significant risk factor for elderly people, and they recommend supplementation to reduce the risk.

Now, if the mention of folic acid and vitamin B12 rings a bell, it may be because you've heard of the beneficial effects of these vitamins, working together - they're highly interdependent - to reduce our blood levels of the amino acid homocysteine, a bad actor in the molecular drama of life. (Folic acid is also well known for its remarkable ability to reduce the incidence of the serious birth defects known as neural tube defects.)

Homocysteine levels increase with age in both men and women. That's unfortunate, because elevated levels are harmful to our health. Homocysteine is strongly implicated in the development of atherosclerosis and, therefore, of heart disease. Atherosclerosis affects not only the coronary arteries but also the cerebral arteries (among many others), so it causes impaired blood flow to the brain. It can also lead to a stroke (a "brain attack"), as can hypertension, although stroke can occur in other ways as well. In any case, atherosclerosis and stroke are two of the main causes of vascular dementia.

FOLIC ACID AND ALZHEIMER'S DISEASE
The Swedish researchers focused on Alzheimer's disease partly because it is far more prevalent than vascular dementia, but partly also because there appear to be links, both direct and indirect, between folic acid and the functioning of brain cells, and thus possibly with the development of Alzheimer's. It has been found, for example, that low levels of folate (the form in which folic acid is usually found in the body) are strongly associated with atrophy of the cerebral cortex.2 And homocysteine, which can be too high if folate is too low, has a neurotoxic effect that could lead to cell death or neurological and psychiatric disorders such as Alzheimer's disease.3,4


There is a connection between
low levels of folate or B
12 and
Alzheimer's disease. And because
all elderly people are at some risk,
it seems prudent for everyone to
supplement with these vitamins.

Furthermore, the researchers point out (with numerous literature citations) that low folate levels have been specifically related to Alzheimer's disease as well as to all other types of dementia and to vascular diseases. In addition, low folate has been associated with specific aspects of cognitive function, and some studies have shown a beneficial effect of folate on memory deficits.

VITAMIN B12 AND ALZHEIMER’S DISEASE
There may also be a vitamin B12 connection with Alzheimer's. In patients with this disease (as well as in patients with other dementias and in people with cognitive deficits compared with control subjects), some studies have found higher prevalences than normal of vitamin B12 deficiency. Other studies, however, have failed to confirm these findings. Furthermore, some studies have shown that supplementation with vitamin B12 is effective in improving cognition in demented or cognitively impaired people - but again, other studies have not confirmed this.

LOW LEVELS OF FOLIC ACID AND VITAMIN B12 ARE RISK FACTORS
It's confusing! Which is why, of course, further studies are always needed, each one chipping away at some aspect of the problem until finally (one hopes) the Truth emerges, like a beautiful statue from a chunk of marble. And that brings us back to the Swedish study.1 The researchers examined 370 elderly (aged 75-101) citizens of Stockholm who were not necessarily in good physical health but who, importantly, were not suffering from dementia of any kind at the outset of the study and who had not been taking vitamin B12 or folic acid replacement therapy. (The absence of dementia was verified through standardized clinical procedures for the diagnosis and evaluation of dementias.)

The subjects were followed for an average of three years to see how many of them did develop cases of clinical dementia (answer: 78, of which 60 were Alzheimer's cases) and how this correlated with their blood levels of vitamin B12 and folate.* In other words, the researchers asked the question: are low levels of these vitamins a risk factor for Alzheimer's? And their answer was yes.


*During the course of the study, 86 subjects died. Examination of their medical records and death certificates revealed eight cases of dementia, and these data were included in the analysis.

They found, however, that the risk was significant - about twice normal, in fact - only when low levels of the two vitamins were considered together, i.e., when the correlation was drawn between Alzheimer's and either of the vitamins, but not when it was drawn between Alzheimer's and just one or the other of the vitamins by itself. In other words, if in these data you look for a correlation between Alzheimer's and low folate alone, you won't find it, and ditto for low vitamin B12 alone. But if you look for a correlation between Alzheimer's and either low folate or low B12, . . . bingo! That means that both of them are important in the Alzheimer's connection.

GOOD COGNITION IS A RISK FACTOR
Furthermore (and this brings us back to the startling fact we sprang on you at the beginning), the researchers found that the correlation between Alzheimer's disease and low folate or B12 was particularly strong - about three times normal - in those subjects who were judged to have "good cognition" according to a standardized test called the Mini-Mental State Examination (MMSE). By contrast, those who scored poorly on the MMSE (with all else being equal, as far as the researchers could tell) were not at any significantly increased risk for Alzheimer's!

So this is how it shaped up: when the risk for Alzheimer's was evaluated for all the subjects as one group, it was twice the norm in those with low folate or B12. But when the risk was evaluated for the subjects grouped according to cognitive function, the risk was three times the norm for the high scorers with low folate or B12, and normal for the low scorers with low folate or B12.

Go figure - and the researchers tried, of course. They reevaluated their data in terms of the living arrangements of the subjects in the two groups. It turned out that those with good cognition were more likely to have been living at home, where they might have had a deficient intake of vitamins because of poor eating habits (especially for those living alone), rather than in an institution, where good nutrition was more or less guaranteed. Correcting for this difference did not change the outcome, however. Nor did correcting for differences between the two groups in terms of the number of meals per day and the number of cooked meals per day that they consumed: still the same outcome.

SUPPLEMENTING WITH VITAMINS CAN REDUCE THE RISK
So it remains a mystery why elderly people with low folate or B12 and good cognition are at greater risk for Alzheimer's - at least in this study - than those who are less fortunate in the cognition department. Will further studies confirm this result? We will have to wait and see. Meanwhile, we know that there is a connection between low levels of folate or B12 and Alzheimer's disease. And because all elderly people are at some risk for Alzheimer's, it seems prudent for everyone to reduce that risk by supplementing with these vitamins, whose safety is unquestioned and whose benefits in other areas, notably the prevention of heart disease, are well established (see the sidebar "Vitamin B12 and Folic Acid").

Vitamin B12 and Folic Acid

Vitamin B12 (cyanocobalamin, also called cobalamin) is the last vitamin to have been discovered (in 1948), and it is still not entirely understood. It contains one cobalt atom - which is why cobalt is an essential trace element - and it is sometimes classed independently of the other B vitamins. It is essential for cell replication and plays a critical role in the production of DNA and RNA. It supports growth, appetite, and the formation of red blood cells and myelin sheaths (the insulating sheaths on nerve fibers). It may also be involved in the production of brain neurotransmitters, and it is used in the treatment of various mental disorders. Getting sufficient B12 is especially important as we grow older, as our ability to absorb it diminishes with age, and it appears to be important for proper immune function.

Folic acid (also called folate) is a B-vitamin that is important in the formation of red blood cells - with the help of vitamin B12 - and the metabolism and utilization of proteins and amino acids. It is vital for all processes involving cell division, and, like B12, it plays a critical role in the production of DNA and RNA. Dietary deficiencies of folic acid, which used to be very common, have been linked to an increased risk of neurological birth defects, so it is now found as a standard additive in cereal grains. Nonetheless, about 10% of the U.S. population is still believed to be deficient in this vitamin,1 and supplementing with it is important not just for women of childbearing age but also for older people, who may not get enough of it in their food. It should always be taken in conjunction with vitamin B12, because too much of one can mask a deficiency in the other.

  1. Ames BN. Micronutrient deficiencies. A major cause of DNA damage. Ann NY Acad Sci 1999;889:87-106.

(A joker might suggest that, just to be safe, you should also try hitting your head with a hammer a few time to, y'know, take some of the sparkle off your cognitive abilities. But that would be dumb, wouldn't it? Besides, I tried it, and it didn't work.)

FOLATE IS A KEY TO HEART HEALTH
As we alluded to above, folate has come to be recognized as a key factor in heart health because of its ability - in conjunction with vitamin B12 - to reduce homocysteine levels. There is no longer any question regarding the strong statistical link between homocysteine and the risk for coronary heart disease (CHD),5 so ensuring that people get enough folic acid in their diet to reduce homocysteine levels has become a matter of public health policy. But how much folic acid is enough?

Since January 1998, the FDA has mandated that all refined cereal grains in the United States be fortified with 140 micrograms of folic acid per 100 grams of product (one microgram is one-thousandth of a milligram).6* Folic acid is found naturally in whole grains, citrus fruits, green vegetables, and beans (but cooking can destroy it). The FDA's Recommended Daily Allowance for folic acid is 400 mcg, and the mandated grain fortification is estimated to have increased the American consumer's average daily consumption of this nutrient by an increment of about 100 mcg (micrograms), or 0.1 mg.


*The primary impetus for this ruling was to reduce the incidence of neural tube defects in newborns, for which the value of folic acid is indisputable.

WOULD MORE FOLATE BE BETTER?
Data from the long-running Framingham Heart Study in Massachusetts show that homocysteine levels in the general population did, in fact, decrease - by 7% - in the first year after the FDA mandate took effect.7 That's good, but it raises three important questions:

1. Does reducing homocysteine levels cause a decrease in the incidence of coronary heart disease events, such as angina, heart attack, or cardiac arrest? The answer is not known, because there are as yet no clinical trial data demonstrating the efficacy of homocysteine-reducing therapy in preventing CHD events. It is widely assumed, however, that this will indeed prove to be the case.

2. What are the effects of the FDA's grain-fortification program likely to be in the longer run?

3. Would a much higher intake of folic acid (together with a correspondingly higher intake of vitamin B12 as well) be better, in terms of saving lives and saving medical costs to society?

MORE FOLIC ACID WOULD SAVE LIVES AND MONEY
To answer the second and third questions above would require a sophisticated analysis of many factors, based on an exhaustive survey of the world's scientific literature on folic acid, vitamin B12, homocysteine, and cardiovascular disease.

Just such a study, published recently in the Journal of the American Medical Association, was undertaken by a group of researchers from the University of California at San Francisco, Tufts University, the Harvard School of Public Health, and the Erasmus Medical Center in Rotterdam, The Netherlands.8

Incorporating powerful statistical tools in their computer model, the researchers crunched all the available data and came to the following conclusions about what would likely occur over the ten-year period from 2001 through 2010:

1. Morbidity/mortality reduced. The existing grain fortification with folic acid would lead to a 13% reduction in heart attacks in men and an 8% reduction in women, with comparable reductions in deaths due to CHD. As mentioned earlier, homocysteine levels increase with age in both men and women, but at any given age, both the homocysteine levels and the risk for CHD are lower in women than in men.

2. Lives saved. If, in addition to grain fortification, all patients in the USA with known CHD were treated with 1 mg (1000 mcg) of supplemental folic acid and 0.5 mg (500 mcg) of vitamin B12 per day to further lower their homocysteine levels, approximately 310,000 fewer deaths due to CHD would occur over the ten-year period, compared with grain fortification alone. (The amount of supplemental folic acid in this treatment regimen is ten times the incremental amount by which the FDA mandate has increased the average daily consumption of folic acid through food.*) The absolute reduction in deaths would be greatest in the older age groups, and men would benefit more than women because men have the higher homocysteine levels and risk for CHD to begin with.

3. Lives improved. If the same treatment regimen just described were given to all men over 45 who did not have CHD, the projected gain over ten years would be more than 300,000 "quality-adjusted life-years" (QALYs). This concept is a statistical measure that tries to take the quality of life, not just its duration, into account (one QALY is defined as one year of perfect health). And if the treatment were given to all women over 55 (a higher threshold age than for the men, for statistical reasons) who did not have CHD, the projected savings would be more than 140,000 QALYs.

4. Money saved. For the treatment regimen just described for men over 45, the projected cost savings over the ten-year period would be $2 billion (in 1997 dollars). Inexplicably, the authors did not estimate the cost savings for the women over 55.


*Actually, it could be argued that the supplemental amount is about 20 times greater than the incremental food amount, because folic acid in supplement form is known to have about twice the bioavailability of folic acid in food, i.e., it is twice as likely to reach the body's cells, where it is needed. Either way, though, you'd have to be a sumo wrestler to eat as much as it would take to get an additional 1000 mcg of folic acid from food alone.

These figures, although they are all hypothetical, command our attention. The authors of the study concluded their report by saying:

The observational evidence supporting high homocysteine levels as a risk factor for CHD events is strong. Furthermore, clinical trial data demonstrate that homocysteine levels can be lowered by inexpensive and safe doses of folic acid and cyanocobalamin. . . . Ultimately, we would recommend homocysteine-lowering therapy routinely only if ongoing clinical trials demonstrate that vitamin therapy reduces clinically important CHD events. In the meantime, since combined therapy with folic acid and cyanocobalamin is well tolerated, it is reasonable to consider routine therapy in men older than 45 years and women older than 55 years.

What more could we add to that?

References

  1. Wang H-X, Wahlin Å, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B12 and folate in relation to the development of Alzheimer's disease. Neurology 2001;56:1188-94.
  2. Snowdon DA, Tully CL, Smith CD, et al. Serum folate and the severity of atrophy of the neocortex in Alzheimer's disease: findings from the Nun study. Am J Clin Nutr 2000;71:993-8.
  3. Hutto BR. Folate and cobalamin in psychiatric illness. Compr Psychiatry 1997;6:305-14.
  4. Nilsson-Ehle H. Age-related changes in cobalamin (vitamin B12) handling. Implication for therapy. Drug Aging 1998;12:277-92.
  5. Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet 1999;354:407-13.
  6. Food Standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Federal Register 1993;58: 53305-12.
  7. Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999;340:1449-54.
  8. Tice JA, Ross E, Coxson PG, Rosenberg I, Weinstein MC, Hunink MGM, Goldman PA, Williams L, Goldman L. Cost-effectiveness of vitamin therapy to lower plasma homocysteine levels for the prevention of coronary heart disease. JAMA 2001;286(8):936-43.

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