Folate, Vitamin B6, and B12 Intakes in Relation to Risk of Stroke Among Men

When we think about the people most at risk of a stroke, we tend to think of the elderly or the unfit. Well, if you have a B-vitamin deficiency, you’re in for a shock: you may also be at risk.

It’s now known that deficiencies in folate, B6, and B12 have been linked to elevated blood homocysteine levels. This can pose serious risks of chronic diseases, including stroke.

The Health Professional Follow-up Study was designed to establish just how intakes of folate and vitamins B6 and B12 could influence ischemic and hemorrhagic stroke¹.

The 14-year study, published in the journal Stroke, involved 43,732 men aged between 40 and 75 who had no history of cardiovascular diseases or diabetes. The men were followed from 1986 to 2000, with dietary assessments taken every four years to calculate their individual nutritional status.

At the end of the study, the participants were divided into quintiles according to their intakes of B vitamins. Their relative risk of stroke was estimated by comparing the incidence of stroke in a particular dietary intake quintile. Elevated risk levels were found with those in the lowest B vitamin intake group.

Results were adjusted to account for other factors that contribute to stroke: cigarette smoking; body mass index (BMI); physical activity; history of hypertension and hypercholesterolemia; aspirin use; and intakes of alcohol, fiber, potassium, vitamin E, and total energy.

The results could have many of us - not just men - rethinking our diet.

When factors such as poor diet, lack of exercise, genetic disorders and other health conditions were accounted for, the risk of stroke was clearly linked to an individual’s intake of folate and B12.

In fact, men in the highest quintile of folate intake had an approximately 30% lower risk of ischemic stroke than those in the lowest quintile.

Intake of vitamin B12 - but not B6 - was also inversely related to risk of ischemic stroke, but not hemorrhagic stroke.

Specifically, it appears that something as simple as a higher intake of folate and vitamin B12 can reduce the risk of ischemic stroke.

But why? And what do these specific B vitamins have to do with stroke?

In recent years, there’s been a lot of research into the link between blood homocysteine levels and stroke.

There is now clear evidence that elevated blood homocysteine concentration increases the risk of stroke, especially among those with high blood pressure.

Homocysteine levels are largely affected² by the methylenetetrahydrofolate reductase polymorphisms (particularly C677T) and folate status . In other words, elevated homocysteine levels tend to be related to either genetic influences or dietary factors: particularly low intakes of folate, vitamin B6, and B12.

Prior to the 1986 study, evidence regarding the influence of B vitamins was relatively sparse. Many previous studies also hadn’t distinguished between hemorrhagic and ischemic strokes, which have significantly different causes.

Ischemic strokes occur when blood flow to the brain is blocked by a blood clot. There are two major types of ischemic stroke: Thrombotic (when a blood clot forms in an artery leading to the brain) and embolic (when a clot forms elsewhere in the body — such as the heart or neck — and travels to the brain).

These are the most common types of stroke, comprising about 87 percent of all cases.

A hemorrhagic stroke occurs when a weak blood vessel bursts and bleeds into the brain. Unlike an ischemic stroke, hemorrhagic strokes begin with a sudden onset headache or head pain.

Hemorrhagic strokes are less common, comprising about 15 percent of stroke cases, but they are often fatal. There are two types of hemorrhagic stroke: intracerebral hemorrhage (a weak blood vessel breaking inside the brain) and subarachnoid (a weak blood vessel breaking on the surface of the brain). 

Here’s where the findings of the 1986 study got interesting. The repeated diet assessments allowed the researchers to examine various temporal associations between intakes of these three B vitamins and the risk of stroke.

It was found that men with higher folate intake exercised more, were less likely to be current smokers or overweight, and were more likely to use aspirin regularly. However, they also drank less and had slightly higher proportions of diagnosed hypercholesterolemia.

Men with higher intake of vitamin B6 were very similar to those with higher folate intake, while men with higher intakes of all three B vitamins (folate, vitamin B6, or vitamin B12) were more likely to take vitamin supplements.

When it came to examining men who were older and/or smokers, it was found that those in the highest quintile of folate intake had a significantly lower risk of ischemic stroke than those who were in the lowest quintile.

Interestingly, folate intake was not related to risk of hemorrhagic stroke. Higher intake of Vitamin B12 intake was shown to reduce the risk of ischemic stroke, but, like folate, appeared to have little impact on the risk of hemorrhagic stroke.

The researchers wondered whether the beneficial effect of folate intake on ischemic stroke could be explained by other health-related factors. It was possible that the men with higher folate intake had an overall healthier lifestyle than those with relatively low folate intake.

However, this was discounted after similar results were found among the men who were older and smokers.

Previous research has already shown a link between low blood concentrations of folate and a higher risk of ischemic stroke. In the First National Health and Nutrition Examination Survey (NHANES I), researchers found those with the highest intake of dietary folate were 20% less likely to suffer from a stroke³. Although the research did not differentiate between ischemic and hemorrhagic, these findings were consistent with the current study.

The men in this large study were typically found to rely on vitamin supplements as a source of folate. In fact, the researchers believed that intakes of folate and vitamin B6 were highly correlated largely thanks to supplements the men were taking as their major sources of folate and vitamin B6.

Homocysteine is a naturally-occurring amino acid created when your body metabolizes the essential amino acid methionine. Methionine is broken down into homocysteine, and then homocysteine is ‘recycled’ back to become methionine again.

Methionine is a sulfur-containing amino acid involved in building proteins and producing certain substances in the body, including the antioxidant glutathione (your body’s greatest antioxidant) and the molecule SAMe. SAMe is a universal methyl molecule that donates a methyl (CH3) group required for the proper function of the cardiovascular system, detoxification pathways, and neurological systems.

So methionine is definitely what you want more of in your body, NOT homocysteine.

A host of important nutrients are created throughout the methionine-homocysteine pathway; all of which play a part in various other biochemical reactions such as detoxification, healthy immune function, the formation of connective tissues, as well as brain and cardiovascular function.

Normally, homocysteine is broken down by your body’s stores of vitamin B12, vitamin B6, and folate and changed into substances that your body actually needs.

But if the body is lacking in any of these nutrients, homocysteine won’t be converted. This results in elevated homocysteine levels and fewer of the beneficial compounds your body needs.

Excess homocysteine levels can lead to one of two serious health issues: inflammation of the blood vessels, and/or oxidative stress.

A study published in the British Medical Journal showed that elevated homocysteine levels in blood plasma increased the risk of death from cardiovascular disease⁴ in older people even more than high cholesterol, blood pressure or smoking.

As explained above, high levels of homocysteine may cause vascular damage due to toxic accumulation in endothelial cells and the generation of free radicals.

Numerous studies have indicated that correct doses of vitamins such as folic acid, vitamin B6, vitamin B12, and betaine may control or alleviate the risk of elevated⁵ homocysteine.

Elevated homocysteine is strongly linked to low levels of plasma folate. There are also links between blood levels of vitamin B12 and pyridoxal-5-phosphate (the active form of B6). Previous studies have also found that elevated homocysteine levels in plasma was an independent risk factor for ischemic stroke.

Unsurprisingly, varying degrees of hyperhomocysteinemia are detectable in all inflammatory diseases. Hyperhomocysteinemia is also considered as a risk factor for inflammatory diseases including life-threatening cardiovascular disease, stroke, renal failure and cancer.

In many cases, inflammation occurs when white blood cells rush to a site of infection or injury in order to fight off pathogens. Chronic inflammation results in a buildup of white blood cells and damage to the surrounding tissues, along with excess deposits inside the blood vessels.

This buildup can ultimately lead to interruption of normal blood flow in the brain: a stroke.

Raised homocysteine affects the way cells use oxygen, causing a buildup of oxidized fats and proteins within developing arterial plaques. This oxidation injury - along with methylation defects and hindered DNA repair due to poor folate metabolism - has also been linked to the development of cancer.

It has also been shown that hyperhomocysteinemia not only is produced from inflammation, but the oxidative stress generated from hyperhomocysteinemia will again promote inflammation. As a result, elevated homocysteine and inflammation markers are frequently being detected at the same time⁶, even if they are not correlated.

Oxidative damage also causes injury to blood vessels, making them more likely to catch sticky material and blood. This increases the risk of blood clots and bleeding.

As found by the researchers in this study, men who were otherwise healthy (i.e. no history of cardiovascular disease or diabetes) were able to reduce their risk of ischemic stroke by taking higher levels of folate and vitamin B12. This finding is supported by other epidemiological and experimental studies on the benefits of folate in preventing ischemic stroke.

But taking any old multivitamin won’t do. There’s another factor at play in the homocysteine pathway: genetics and MTHFR.

A mutation in the MTHFR gene - particularly SNP (single nucleotide polymorphism) C677T not only contributes to elevated homocysteine, but also to the risk of Vitamin B12 deficiency. MTR and MTRR variants are other genetic SNPs which may significantly impact the conversion and absorption of B12 in the body as well as folate and other nutrients.

It’s for this reason that only a bioactive form of folate and vitamin B12 is crucial to overall wellbeing and prevention of chronic disease.

Folate is the natural active form of vitamin B9 in food. Folate is vital to your health no matter what age you are or what stage of life you’re at. It’s required for many different functions within the human body, particularly the production of red blood cells. Folate occurs naturally in many foods such as legumes and leafy greens.

Deficiency or low levels of folate can be caused by genetics, certain diseases, medications, or by not obtaining folate from your food.

One of folate’s most crucial roles is in ridding the body of excess homocysteine. Ordinary folic acid supplements will not provide the full spectrum of effects if an individual is unable to convert folate to its biologically active form called 5-methyltetrahydrofolate (5-MTHF) or L-Methylfolate.

Because a large proportion of the population has the genetic enzyme deficiency that prevents the proper conversion of folate to 5-MTHF, many people are vulnerable to low blood folate levels and subsequently, higher than desired homocysteine (even if they take a folic acid supplement daily).

For this reason, taking bioactive folate 5-MTHF directly has been shown to significantly increase blood serum folate levels compared with folic acid supplementation.

Key point: This form of folate is vital for people who have a genetic enzyme deficiency because it requires no conversion to become metabolically active.

Folic acid, on the other hand, is the synthetic (man-made) form of folate that is added to fortified foods or dietary supplements.

Some of the best methylfolate supplements for vegans, those with cardiovascular risks, or MTHFR mutations include Methyl-Life® products (B-Methylated II, Methylated Multivitamin, also Methylfolate 7.5+ or Methylfolate 15+ if you suffer from depression).

These have been created by a team of natural health experts and used successfully by hundreds of people all over the world. It’s worth noting that Methyl-Life® recently received data from a study that showed theirs to be the purest, stable, and most potent of four of the world’s industry-leading, patented L-Methylfolates. Check out the study comparison details to learn more.

B12 works closely alongside folate to help make red blood cells which are required for carrying oxygen to all parts of your body. It’s also required to keep homocysteine levels from becoming elevated.

Normally, homocysteine is broken down by your body’s stores of vitamin B12, vitamin B6, and folate and changed into substances that your body actually needs. However, a lack of any particular nutrient can lead to an undesirable elevation in homocysteine levels and a lowering of the ‘good and necessary’ compounds your body requires.

Vitamin B12 also plays a major role as a cofactor in the methylation process of L-methylfolate, and is then required for the conversion of homocysteine to methionine. The conversion of homocysteine to cysteine also requires B-6 (specifically pyridoxal-5-phosphate).

Vitamin B12 is also crucial for proper brain development and the one-carbon metabolism required for transmethylation reactions in the recovery of methionine from homocysteine. It’s also involved in the formation of S-adenosylmethionine (SAMe) which we know to be the neurotransmitter generator - so this is a key nutrient to take along with L-Methylfolate for maximum effect against mood disorders, particularly depression.

Vegans are especially at risk of high homocysteine due to their low B12 intake (since dietary B12 comes mainly only from animal-based foods). The good news is that taking the right B12 supplements can effectively reduce homocysteine levels. One study showed⁷ that taking 500 mcg/day of vitamin B12 for two months was able to reduce elevated homocysteine levels to less than 5 µmol/.

Similarly, another study showed that vegans whose intake of B12 averaged 5.6 mcg/day had homocysteine levels of 7.9 µmol/l, which was slightly lower than those with normal B12 levels⁸.

Supplementation with a highly bioavailable form of vitamin B12 5,000 mcg is the most efficient way to ensure optimal levels quickly. This is particularly important for vegans/vegetarians, the elderly, and anyone who is unable to absorb B12 efficiently.

Methy-Life’s® B12 Complete is ideal for people who have MTR, MTRR, COMT, or other gene mutations that may be affecting B12 absorption. B12 Complete contains a combination of the 3 most bioactive forms of B12 (hydroxocobalamin, methylcobalamin and adenosylcobalamin) for maximum delivery and absorption.

The B12s within this supplement have already been converted into forms that can be absorbed and used by the body’s cells immediately. This truly is a full-spectrum B12 product.