Medicine For People!

September 2006: Brain Health as We Age: Part Seven – Homocysteine, Folic Acid and Vitamin B-12

Introduction and Review

Dear Reader,

This month we return to our series of newsletters on brain aging to discuss homocysteine, folic acid, and vitamin B12.

Because factors affecting brain health are many and complex, we are presenting the information in separate articles over a period of months. At the end of this series, we will outline a plan to help you maintain your mental function as you age. Because this plan will differ in many regards from what you may be reading elsewhere, we want to give you a detailed picture of the brain - how it is structured and how it works - so that you will have all the information you need to evaluate this or any other plan.

Review of Previous Newsletters

  1. The brain is different from all other tissues of the body in the complexity of its structure and its intricate web of tiny nerve tendrils.
  2. These create a massive appetite for energy production.
  3. When that energy production is impaired, brain tissue is destroyed. Certain nutrients can provide a protective cushion.
  4. Impairment of blood flow can interfere with brain function.
  5. One mechanism of brain damage is microinflammation. First, this impairs thinking by interfering with circulation of the blood. Second, microinflammation directly damages nerve tissue.

Turning Food into Brain Cells

Look at that food on the table. Eat that food, and the biochemical plant inside you transforms it into, among other things, your brain. However, there is many a slip between the cup and the lip. If conditions are less that optimal during the food-to-brain transformation, too much of the amino acid homocysteine is formed – and that is not good.

Figure 2: A healthy supper

Figure 3

The Methionine - Homocysteine Cycle

Homocysteine is a metabolic byproduct of the amino acid methionine. Methionine is an essential amino acid, meaning that we need it but our body doesn't make it, so we must get it from food, such as eggs, fish, poultry, sesame seeds, or seaweed.[1]

Think of methionine as a loaded rivet gun. It uses its biological rivet to change food molecules so they can be used to make bodily tissues. After it "shoots its rivet," methionine becomes homocysteine and, like an empty rivet gun, is unable to do any more metabolic work.


Above you can see methionine on top, with its "rivet" to the left, then below, after the job is done, the leftover homocysteine.

Homocysteine presents two problems. First, if we do not recycle it properly, we can run low in methionine and fail to perform crucial metabolic functions, such as repair and maintenance of neurons in our brain. Second, like an empty rivet gun, it clutters up the shop. Homocysteine has a molecular shape that actually harms tissues of the body if it is not recycled.[2]

Homocysteine and the Brain

Over the past twenty years doctors have learned that high blood levels of homocysteine are associated with coronary disease. Many cardiologists advise their patients to take B vitamins to prevent this.

It is less well-known that homocysteine also affects our brains. Numerous studies show that people with higher levels of homocysteine not only develop Alzheimer's dementia [3] more frequently, but are also more prone to mild memory losses.

Homocysteine damages the brain in at least five different ways.

This image from the New England Journal of Medicine (N Engl J Med 2002; 346:466-468) is reproduced by permission. Copyright ©2002 Massachusetts Medical Society. All rights reserved.

  1. Homocysteine damages the vessels that carry blood to the brain. MRI's show more "silent" strokes in people with higher levels of homocysteine.[4] Blood vessels generally age from the inside out, as detailed in our June newsletter. The endothelium (lining of the vessels) takes the impact of fats, toxins, and other substances passing through the blood, including homocysteine. Homocysteine directly damages the endothelium, and the more homocysteine we have floating around, the worse for our blood vessels.

  2. Homocysteine enhances the formation of proteins in the brain called beta-amyloid peptide. Generally present in small amounts, these proteins accumulate in people with Alzheimer's disease, damaging neurons.. Microscopic evidence of beta-amyloid peptide in the brain on autopsy is one defining characteristic of Alzheimer's.

  3. Excess homocysteine signals brain cells to self-destruct, a process called apoptosis[5]. Each cell in our body continuously monitors its own function and is programmed to destroy itself if it is damaged, if it appears likely to reproduce abnormally, or if it is simply at the end of its life cycle. Decrease the tendency to apoptosis and we can develop cancer. Increase the tendency and we can lose brain function.

  4. Homocysteine has toxic byproducts. In our March 2006 newsletter we explained that inside our cells we have tiny power houses called mitochondria. Mitochondria produce energy to keep us going. We also noted that mitochondria are particularly prone to oxidative damage from free radicals and that antioxidants reduce this damage. Homocysteine comes into play here as well. If all goes well, we transform some of our homocysteine into a protective substance in the mitochondrial membrane called thioretinaco.[6] As we age, this process slows, and a toxic byproduct called homocysteine thiolactione becomes more prevalent. Homocysteine thiolactone damages every cell in the body by poisoning energy processes. It also speeds the development of cancer, arteriosclerosis and auto-immune illness.

  5. Some of the homocysteine is transformed into homocysteic acid, which over-excites neurons[7]. Methamphetamine is possibly the most notorious substance that overexcites neurons, but there are many such substances, all of which can damage the brain. Neurons are delicate little creatures. Overstress them and they may undergo apoptosis. Homocysteic acid, too, contributes to accumulation of beta-amyloid protein within neurons.[8]'}

Homocysteine, B-Vitamins, and Dementia

Homocysteine is produced constantly, and your body uses vitamins B12, B6 and folic acid to recycle that homocysteine back into methionine. Doctors often will mention vitamin B12 and folic acid in the same breath, because deficiency symptoms overlap and the two vitamins work together in many situations. All three vitamins are important in the recycling of homocysteine into the beneficial methionine and thioretinaco. This is why one of our key recommendations will be to take vitamins B12, B6 and folic acid to reduce levels of homocysteine and reduce aging of the brain.

It is possible that folic acid and vitamin B12 have a beneficial effect on the brain aside from lowering homocysteine. Scientists are still arguing about that question. The graph below shows that those with the highest levels of folic acid suffered the smallest incidence of dementia, about 8 percent, compared to 22 percent of those with the lowest levels.[9] (The numbers to the right of each curve show the serum level of folic acid.) We know folic acid stabilizes DNA in the cell, which improves cell function. It also lowers homocysteine if it is high. Folic acid appears to improve the function of the endothelium (thereby improving circulation to the brain) when that dysfunction is due to high levels of homocysteine.[10] We know that folic acid helps and homocysteine hurts, but the academicians are still fighting over the deta ils.

Source: Ann Neurol 2002; 51:285

The study above showed that the less folic acid in the blood, the more likely a person was to develop dementia. Can you get the same effect from taking folic acid supplements?

My answer is yes. There are numerous studies that support the value of these supplements. As an example, the Veterans Administration studied 321 well-educated men aged about 65. Some took supplemental vitamins, some did not. Over the years, men with higher intakes of folic acid, vitamin B12, and vitamin B6 scored better on tests of memory and other cognitive functions than did men who had lower intakes. Men who had higher levels of these vitamins in their blood, regardless of what they ate, did better as well. Over a period of three years, those men with the average to high levels of homocysteine scored more poorly on memory tests, while those with the lowest levels actually improved.[11]

Vitamin B12 and Folic Acid Work Together

Neurologists and psychiatrists have known for decades that vitamin B12 and folic acid deficiency can lead to dementia. In Sweden in 2001, doctors reported on a group of 370 smart, healthy Swedes, age 75+, none of whom were taking B12 or folic acid supplements. They measured blood levels of these vitamins and, after three years, had a separate group of doctors examine each patient for the development of Alzheimer's dementia. In those patients with low levels of either vitamin, twice as many developed Alzheimer's as did the patients with normal levels of these vitamins.[12]

Vitamin B12 Deficiency - A Hidden Epidemic

When we age, we may not show the classic symptoms of vitamin B12 deficiency, such as anemia and numb feet. Vitamin B12 deficiency can cause depression, mania, psychosis, and paranoia. Our only symptom may be mental decline, and most often patients, together with their families and doctors, consider that mental decline as a normal part of aging. We may take vitamin B12 supplements or consume B12 in meat and eggs, and still be deficient because we do not absorb it. One-third to one-half of elderly people fail to make enough stomach acid, and stomach acid is required to assimilate B12. Elderly people can even pass a standard blood test or a Schilling test[13] and still be vitamin B12 deficient.[14] In the US, authorities teach that levels of B12 as low as 200 picograms/milliliter are normal, whereas in Japan, anyone with a level below 500 is considered B12 deficient and treated as such.[15] Maybe if we share this information with General Motors, they'll be able to compete better.

Current medical journal articles sometimes counsel "go slow" when considering blanket recommendations for folic acid and vitamin B12. Consider this, though:

  • Women, especially younger women, who consume more folic acid either in their diet or from supplements, have about half the risk of hypertension as do women who consume the least.
  • In both genders, lower levels of homocysteine reduce the risk of stroke and heart attack.
  • Following a two-decade battle, the federal government mandated folic acid fortification of certain foods to prevent birth defects caused by folic acid deficiency. The British showed that even higher levels would be more effective.
  • Folic acid reduces the risk of breast cancer, uterine cancer, hip fractures in the elderly, and many other conditions beyond the scope of this article.
  • The vitamin B12 molecule can appear in inactive forms that falsely elevate the standard blood analysis for vitamin B12 into the normal range. Blood levels of homocysteine and methylmalonic acid are required if we wish to be certain about B12 status. These two tests total about $300. Since symptoms of B12 deficiency can be vague, and since people who are treated within six months of the onset of their symptoms respond best, prevention is preferable.

How to Lower Homocysteine

Don't Smoke

Because smoking lowers level of folic acid, cessation of smoking reduces homocysteine and therefore rate of aging and loss of cognitive function. People who are depressed face an even greater risk.[16]

Exercise and Eat Well

People over sixty-five years old who have a greater degree of microinflammaton have a higher level of homocysteine, even with normal levels of vitamins B6, B12, and folic acid.[17] So, all you seniors: exercise and fresh food are good for you. You juniors: now is the time to develop good habits.

Think About Coffee and Alcohol

Coffee raises homocysteine, but lowers the risk of Parkinson's disease and diabetes. Alcohol lowers homocysteine, but continues to ruin many lives. If you drink either beverage, be moderate.

Respect the Egg

Eggs contain choline, another B vitamin, which importantly supports healthy membranes in the brain. Choline changes into betaine, which helps recycle homocysteine into methionine.

Lest you worry about cholesterol, remember that your liver makes four to eight eggs worth of cholesterol a day, so for most people, cholesterol in their diet is not the problem.

Studies show that two eggs a day will not increase cholesterol in the vast majority of people.

Take Your Vitamins

The Recommended Daily Allowances were originally set as the levels necessary to prevent florid vitamin deficiency syndromes, such as scurvy, rickets, pellagra, and so on. They do not take individual variation into account, nor the idea that increased levels of vitamins can retard aging processes.

We all know people who lived to a great age with no mental deterioration. Many authorities say "All you need is a healthy diet; that will give you all the vitamins you need."[18]

I emphatically disagree. We know that up to half of the population have somewhat slower acting versions of enzymes called catechol-o-methyltransferase (COMT) and methyltetrahydrofolate reductase (MTHFR), and so these people will run somewhat higher levels of homocysteine and lower levels of folic acid. Vitamin B12 deficiency affects at least one in six people in the 67 to 90+ year old age group.[19] White men are more susceptible than blacks or Asian women. The genetic differences that lead some people to have higher levels of homocysteine are well described. Within the next few years, laboratory tests for these genetic variants should become much more available and affordable. Right now, tests of COMT and MTHFR cost $360.[20]

I suggest a high potency B vitamin, plus about 5 milligrams of folic acid, to keep your homocysteine at as low a level as possible. Women in the child-bearing years are less likely to produce a child with a neural tube defect with this dose of folic acid[21]. Five milligrams equals 5000 micrograms, and folic acid is available only in tablets up to 800 micrograms. We have a liquid solution; one drop contains 5000 micrograms of folic acid. If you are pregnant, ask your doctor's advice about any supplements you take.

In addition, vitamin C, 1000 milligrams per day, prevents homocysteine from damaging the endothelial lining of the bood vessels.[22]

Now and the Future

Pharmaceutical researchers are pushing hard to design something that might prevent or treat dementia. Until then, lifestyle and nutrition seems to offer the most promise. When our series continues next month, we'll talk about the membranes surrounding brain cells and about phosphatidyl-serine and other nutrients that preserve function of those membranes.


[2] For more information on the methionine/homocysteine cycle, you may read a brief review at, a long review at , and the full-tilt biochemical exposition by the world expert on homocysteine at

[3] For example, in one Italian study of more than 800 people over the age of 65,researchers obtained homocysteine levels, then counted up the number of people who developed dementia.

In this graph, no one had dementia at the start of the study, so all the lines begin at 0 percent dementia on the vertical axis. The line marked by hollow diamonds tracks the 217 people with the highest levels of homocysteine. Five years after observation began, about 25% developed dementia. The line marked by black circles tracks the 211 people with the lowest levels of homocysteine. Five years after observation began, about 5% had developed dementia. People with intermediate levels are tracked by the other two lines, and developed dementia at moderate rates.

This study was published in Ann Neurol 2002; 51:285

[4] Ann Neurol 2002; 51:285

[6] The word thioretinaco is shorthand for the sulfur in homocysteine, retinoic acid (vitamin A), and cobalt (in vitamin B12). These are the ingredients of thioretinaco which crucially protects our mitochondria from damage of aging. You biochemistry fans can read more at

[7] N Engl J Med 2002 Feb 14; 346:466

[8] J Neurosci Res 2005 Jun 15;80(6):869-76

[9] Am J Clin Nutr 2005;82:636

[10]Van den Berg M,Boers GH,Franken DG,Blom HJ,Van Kamp GJ,Jakobs C,Rauwerda JA,others. "Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease." Eur J Clin Invest. 1995 Mar;25:176-81. (Issue number 3) =13147= = Author's abstract: Hyperhomocysteinaemia, defined as an abnormally high plasma homocysteine concentration after an oral methionine load, is common in young (< or = 50 years) patients with peripheral arterial occlusive disease. It is thought to predispose to atherosclerosis by injuring the vascular endothelium. Treatment with pyridoxine and/or folic acid may lower plasma homocysteine levels. In mildly hyperhomocysteinaemic patients with peripheral arterial occlusive disease, we studied the effect of daily treatment with pyridoxine (250 mg) plus folic acid (5 mg) on homocysteine metabolism (i.e. plasma concentrations in the fasting state and after methionine loading, in 48 patients) and on endothelial function (in 18 patients). Endothelial function was estimated as the plasma concentrations of the endothelium-derived proteins, von Willebrand factor (vWF), thrombomodulin (TM), and tissue-type plasminogen activator (tPA). At baseline, fasting homocysteine levels were above normal in 24 of the 48 patients (50%); post-load levels, by definition, were above normal in 100% of patients. After 12 weeks of treatment, fasting and post-load levels were normal in 98 and 100% of patients, respectively. Endothelial function was assessed in 18 patients who completed 1 year of treatment. At baseline, median vWF (235%) and TM (57.1 ng mL-1) levels were above normal. At follow-up, vWF levels had decreased to 170% (P = 0.01) and TM levels had decreased to 49 ng mL-1 (P = 0.04). tPA levels were normal at baseline and did not change. Endothelial dysfunction is present in young patients with peripheral arterial occlusive disease and hyperhomocysteinaemia. Pyridoxine plus folic acid treatment normalizes homocysteine metabolism in virtually all patients, and appears to ameliorate endothelial dysfunction.

[11] Am J Clin Nutr 2005;82:627

[12] Neurology. 2001 Nov 13;57(9):1742-3

[14] Age and Aging 1996; 24:536

[15] Medical Hypotheses 1991; 34:131

[16] Neuro Endocrinol Lett 2005 Jun;26(3):261-3

[17] Am J Clin Nutr 2005: 82:335

[18] For example, a recent study in the American Journal of Clinical Nutrition (2005; 81:1155) showed that vitamins B12, B6, and folic acid did reduce homocysteine but did not improve mental function. However, the study ran only four months. The authors did conclude "This might have been due to irreversible or vitamin-independent neurocognitive decline or to an insufficient dose or duration of vitamins."

[19] Am J Clin Nutr 1994; 60:12

[20] Neurogenomics panel available at our office.

[21] Lancet 2001 Dec 15; 358:2069

[22] Chambers JC,McGregor A,Jean-Marie J,Obeid OA,Kooner JS. "Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia: an effect reversible with vitamin C therapy." Circulation. 1999 Mar 9;99:1156-60. (Issue number 9) =13094= = Conclusion: We conclude that an elevation in homocysteine concentration is associated with an acute impairment of vascular endothelial function that can be prevented by pretreatment with vitamin C in healthy subjects. Our results support the hypothesis that the adverse effects of homocysteine on vascular endothelial cells are mediated through oxidative stress mechanisms. = Author's abstract: BACKGROUND: Hyperhomocysteinemia is a major and independent risk factor for vascular disease. The mechanisms by which homocysteine promotes atherosclerosis are not well understood. We hypothesized that elevated homocysteine concentrations are associated with rapid onset endothelial dysfunction, which is mediated through oxidant stress mechanisms and can be inhibited by the antioxidant vitamin C. Methods and RESULTS: We studied 17 healthy volunteers (10 male and 7 female) aged 33 (range 21 to 59) years. Brachial artery diameter responses to hyperemic flow (endothelium dependent), and glyceryltrinitrate (GTN, endothelium independent) were measured with high resolution ultrasound at 0 hours (fasting), 2 hours, and 4 hours after (1) oral methionine (L-methionine 100 mg/kg), (2) oral methionine preceded by vitamin C (1g/day, for 1 week), and (3) placebo, on separate days and in random order. Plasma homocysteine increased (0 hours, 12.8+/-1.4; 2 hours, 25.4+/-2.5; and 4 hours, 31. 2+/-3.1 micromol/l, P<0.001), and flow-mediated dilatation fell (0 hours, 4.3+/-0.7; 2 hours, 1.1+/-0.9; and 4 hours, -0.7+/-0.8%) after oral L-methionine. There was an inverse linear relationship between homocysteine concentration and flow-mediated dilatation (P<0. 001). Pretreatment with vitamin C did not affect the rise in homocysteine concentrations after methionine (0 hours, 13.6+/-1.6; 2 hours, 28.3+/-2.9; and 4 hours, 33.8+/-3.7 micromol/l, P=0.27), but did ameliorate the reduction in flow-mediated dilatation (0 hours, 4. 0+/-1.0; 2 hours, 3.5+/-1.2 and 4 hours, 2.8+/-0.7%, P=0.02). GTN-induced endothelium independent brachial artery dilatation was not affected after methionine or methionine preceded by vitamin C.



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Medicine for People! is published by Douwe Rienstra, MD at Port Townsend, Washington.