Life Extension Magazine®

Example of blood vessel that has an excess of homocysteine

Newly Identified Risks Of Excess Homocysteine

Elevated homocysteine is a proven risk factor for vascular disease. New studies show it may damage the brain even more. A significant proportion of Americans have a genetic defect that predisposes them to high homocysteine. Proper blood testing can readily identify these individuals who, for the first time, are able to obtain a high-potency form of activated folate without a prescription.

Scientifically reviewed by Dr. Gary Gonzalez, MD, in August 2023. Written by: William Faloon.

William Faloon
William Faloon

Few debates expose the inability of mainstream medicine to recognize disease causation more than the homocysteine controversy.

No one disputes that homocysteine is toxic to our inner arterial lining.1,2

No one disputes that arterial disease is the leading cause of disability and death.3,4

If we are to achieve healthy longevity free from heart failure,5-8 stroke,9-11 and dementia,12,13 we cannot allow our bodies to be poisoned by excess homocysteine blood levels.

The debate about homocysteine and atherosclerosis dates back to 1968. Compared to previous medical controversies, this 47-year time interval may appear trivial.14

For instance, bloodletting began around 500 B.C. and became near universal standard of care before the medical establishment rejected it in the early 20th century. The number of deaths caused by physician-induced bloodletting was astronomical, yet it took 2,500 years to figure this out.15,16

The problem today is that doctors are overlooking health risks associated with elevated homocysteine, despite new scientific studies documenting dangers that extend beyond increased heart attack risk.17-21

A significant proportion of Americans have a genetic defect that predisposes them to high homocysteine.22-25 The exciting news is that proper blood testing can readily identify these individuals so they can take one simple step to slash their homocysteine down to a safe range.

In 1981, we advised our members to keep their homocysteine levels low to protect against heart attack and stroke. At the time, there were only 12 published studies available to make this recommendation, yet we were confident in the strength of the data 34 years ago.1,2,7,8,26-33

Newly Identified Risks Of Excess Homocysteine  

Move forward to the year 2015 and more than 2,000 published studies are found when searching “homocysteine and heart disease” on the National Library of Medicine database.

What happened between 1968 and 2015 shows how challenging it can be for the medical establishment to adopt new concepts into standard practice. When studies were conducted on high-risk patients using standard B vitamins to modestly lower homocysteine and anticipated benefits did not occur, doctors declared that homocysteine was not a risk factor for vascular disease.

The problem with these studies is that they were seriously flawed. In 2010, we meticulously exposed defects in these studies to demonstrate how meaningless they were to individuals who took steps to properly lower their homocysteine levels.17

Since our original rebuttals to the flawed homocysteine reports, newly published research further corroborates our long-standing position about the risks posed by excess homocysteine.

For example, a study published in 2014 took a closer look at previous work that proclaimed no benefit to lowering homocysteine. This more detailed analysis revealed a 24% reduced risk of stroke, heart attack, and death in patients older than 67 years given high-dose B vitamins to lower homocysteine.34 This finding makes sense based on the fact that modestly elevated homocysteine does not usually create arterial disease early in life; i.e. it takes decades for damage to our endothelial lining to manifest as frank vascular disease.

A more striking risk reduction occurred in a clinical trial of elderly individuals published in 2014 who received a statin drug (pravastatin) to lower their cholesterol levels versus placebo. Patients in the placebo group with high homocysteine showed a 1.8-fold higher overall risk of developing fatal and nonfatal coronary heart disease.35

Role Of Homocysteine In Vascular Dementia

The scientific community now largely accepts the role of homocysteine in heart disease. What’s overlooked is the adverse impact of elevated homocysteine on short-term memory and dementia risk.

A study published in 2014 evaluated a group of people (average age 64) with vascular cognitive impairment, but who were not demented. After only one year, patients with high homocysteine showed a 4.2-fold increased rate of clinically diagnosed dementia.36

High blood pressure was an even greater determinant of who progressed to vascular dementia, which led the authors of this study to conclude that patients with vascular cognitive impairment “should receive vigorous controls of hypertension and high homocysteine.”36

Another 2014 study looked at people with high homocysteine and uric acid and found a startling 10.5-fold greater risk of vascular dementia.12 The authors of this study noted that elevated levels of homocysteine and uric acid are both well-known risk factors for cardiovascular disease, so it is not surprising that they also contribute to vascular dementia (neurovascular disease).

A 2013 study found that patients with vascular dementia exhibit particularly elevated levels of plasma total homocysteine” and suggested that homocysteine may serve as a marker for the disease in addition to it being a contributing factor.13

When entering the term “homocysteine and vascular dementia” into the National Library of Medicine database, more than 240 published studies can be found dating back to the year 1992.

Does Homocysteine Increase Alzheimer’s Risk?

As we have published in this magazine over the years, vascular dementia and Alzheimer’s disease are often intertwined.37-40 What happens is that capillary blood flow is impaired as a result of the endothelial damage caused by excess homocysteine. Beta-amyloid plaques then appear in these blood flow-deprived areas of the brain.41,42 The result in many cases is clinically diagnosed Alzheimer’s disease.9,18,43,44

Studies show that homocysteine may be toxic to brain cells, in addition to disrupting cerebral blood flow. A systematic review of published studies starting in 1990 and extending to 2012 found that high homocysteine increased Alzheimer’s risk by 1.93-fold, whereas physical activity and omega-3 fatty acids conferred a protective effect.45

A 2013 review looked at the effects of lowering homocysteine for the purposes of protecting against mild cognitive impairment and Alzheimer’s. Based on findings from several previous studies, these researchers concluded that treating patients with B vitamins to lower homocysteine could “prevent or delay cognitive decline and Alzheimer’s disease.”46

Homocysteine alone is not the sole cause of age-associated cognitive decline or Alzheimer’s, but it appears to be a significant contributory factor.

There remains an open controversy as to whether mere treatment with B vitamins will protect against Alzheimer’s. You’re going to learn later in this article why conventional B vitamins don’t always provide necessary homocysteine-lowering effects.

Homocysteine Worsens Diabetic Complications

Newly Identified Risks Of Excess Homocysteine  

Based on a recent report from the CDC, 86 million Americans age 20 and older were found to have prediabetes.47 This is diagnosed when fasting blood glucose levels are in the 100 to 125 mg/dL range.48 Optimal fasting glucose is under 86 mg/dL.

During the prediabetic period before frank type II diabetes is diagnosed, substantial damage to the arterial lining occurs.49,50 This is attributed to the widely fluctuating levels of after-meal glucose and insulin suffered by prediabetics and explains why diabetic complications often manifest before frank type II diabetes is diagnosed.

A 2014 study looked at cardiovascular risk factors beyond glucose and hemoglobin A1C in prediabetics and found that homocysteine and blood thickness are significantly higher in prediabetic patients compared to controls.51 The authors suggested that homocysteine and blood viscosity be used as markers in prediabetics to identify subclinical cardiovascular disease and take preventive measures before a heart attack or stroke manifests.

Another 2014 study cited previous research showing that high homocysteine levels are correlated with increased mortality in type II diabetic patients.52 The researchers then looked at the impact of high homocysteine and type II diabetes in experimental models and found that endothelial damage inflicted by high glucose is worsened by high homocysteine blood levels.

Peripheral neuropathy is a common complication of diabetes that is associated with poor glycemic control.53 Recent clinical studies reveal that high homocysteine exaggerates the prevalence of peripheral neuropathy in diabetics and exacerbates preexisting diabetic neuropathy.54-57

In a community-based study of 483 adults, a high prevalence of peripheral neuropathy was observed among undiagnosed diabetics.54 After an analysis that controlled for age, it was found that low education, hemoglobin A1C, smoking, and elevated homocysteine were independently associated with peripheral neuropathy.54 The role of high homocysteine as an independent risk factor associated with increased prevalence of diabetic neuropathy has been supported by other clinical studies.55,56,58,59

The take-home lesson for anyone with glycemic control issues is that aggressively lowering homocysteine is of the utmost importance. Just as important are comprehensive blood tests to evaluate vascular markers (like C-reactive protein) that doctors today don’t normally associate with diabetic complications.

Cerebral Circulatory Deficit

Cerebral Circulatory Deficit  

Normal aging results in diminished capillary blood flow to the brain. The medical term for reduced blood flow is “hypoperfusion” and it has been implicated in premature brain aging and neurodegenerative disease.60-64

A 2014 study identified excess homocysteine as a specific marker for reduced cerebral perfusion in a group of healthy subjects aged 50 to 75 years.65 The findings corroborate previous research associating high homocysteine with diminished capillary blood flow in the brain.9

Another 2014 study looked at the carotid arteries, which are the largest blood vessels feeding the brain. When factoring in other independent variables such as LDL-cholesterol, hemoglobin A1C, and C-reactive protein, homocysteine was the strongest predictor of carotid blood flow resistance in men older than 65.66 This finding is corroborated by previous research showing elevated homocysteine to be significantly associated with carotid artery disorders.67-69

Aging robs the brain of vital blood flow through occlusion of the large carotid arteries extending from the base of the neck into the brain. Cerebral circulation is further impaired by blockage of microscopic capillaries that feed individual brain cells. Elevated homocysteine damages the carotid arteries69,70 and cerebral capillaries, thus depriving the brain of critical blood flow in two lethal ways.71-73

Homocysteine Damages the Endothelium
Homocysteine Damages the Endothelium

The delicate inner lining or our arteries is called the endothelium.

Damage to the endothelium initiates changes that predispose us to atherosclerosis and its related vascular diseases, including hypertension.81-83

As our endothelium becomes increasingly damaged, occlusive arterial disease can manifest in our coronary arteries, cerebral arteries, and arteries throughout the body including in our kidneys and peripheral nerves.84-92

As it relates to hypertension, endothelial dysfunction impairs vascular expansion and can suppress production of vital endothelial nitric oxide.93-95

As it relates to acute heart attack or stroke, endothelial dysfunction can promote the development of thrombosis (clotting inside blood vessels).96-98

Elevated homocysteine is a factor that causes damage to the endothelium. It does this by promoting the formation of free radicals, impairing the synthesis and function of vasodilating factors in the vascular wall, injuring endothelial cells, and impeding production of structural components in the vascular wall.99-109

In addition, high levels of homocysteine contribute to the undesirable modification of LDL and HDL particles, inflammation, and disorders in coagulation and fibrinolysis (dissolving of abnormal arterial blood clots).93,110,111

Excess homocysteine is both an initiator112,113 and promoter114,115 of systemic endothelial dysfunction, which is the major mechanism behind the development of vascular diseases.116

Our Shrinking Brains

An increased rate of brain atrophy (shrinkage) is often observed in elderly people, especially in those who suffer from cognitive decline.74,75

A study published in 2010 evaluated a group of people over age 70 with mild cognitive impairment to ascertain if lowering homocysteine with B vitamins would reduce the rate of brain shrinkage measured by MRI scans. The results showed that compared to the placebo arm of the study, those taking the B vitamins showed almost 30% less brain shrinkage.74

In patients in this study with higher baseline homocysteine levels (>13 µmol/L), treatment with B vitamins resulted in a remarkable 53% lower rate of brain atrophy. What this finding suggests is that those with higher homocysteine levels suffer greater brain atrophy and derive greater benefit when homocysteine levels are brought down. This study showed that greater rate of brain atrophy resulted in lower cognitive test scores.74 The authors of the study concluded:

The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins…
Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer’s disease, trials are needed to see if the same treatment will delay the development of Alzheimer’s disease.

Move forward four years to 2014 and a study was published whereby researchers looked at the impact of homocysteine on hippocampal volume in a group of elderly patients with varying degrees of cognitive function. After ruling out other known causes of brain atrophy, homocysteine was deemed to be independently associated and significantly involved with hippocampal volume shrinkage.76 This led the researchers to conclude that high homocysteine has a “direct adverse effect” on hippocampal volume.

The hippocampus is the part of the brain that is involved in forming,77 organizing,78 and storing memories.79,80 Based on these findings, the adverse impact of elevated homocysteine on hippocampal volume is depriving aging individuals of the ability to form new memories and connect emotions and senses with past memories, and is placing individuals with high homocysteine at greater risk of dementia.

Yet homocysteine blood testing is still not being routinely done in the clinical setting, which is needlessly condemning large segments of the aging population to cognitive impairment, dementia, and loss of independence.

Surviving A Stroke

Homocysteine is a risk factor for suffering a stroke,117,118 but the impact of high homocysteine on the neurological deterioration that occurs after a stroke was not known until recently.

Recovery from an ischemic stroke is highly dependent on the brain’s ability to survive the temporary loss of blood flow. Without recovery, the outcome is paralysis or death.

A 2014 study assessed whether an association existed between elevated homocysteine and neurological deterioration in patients with acute ischemic stroke. A total of 396 stroke patients were studied. The results showed that high homocysteine levels were independent predictors for poor outcomes in these acute stroke victims.10

Most striking about this study was what the researchers defined as “high” homocysteine blood levels. In patients with homocysteine levels above 10.3 µmol/L, there was a 3.45-fold increase in independent predictors of early neurological deterioration.10

Conventional medicine does not believe homocysteine poses a health problem until blood levels exceed 15 µmol/L.119 Yet this randomized double-blind, multicenter trial showed that homocysteine levels over 10.3 µmol/L markedly worsened outcomes for stroke victims. The conclusion by the authors of this study was simple and to the point:

Patients with acute stroke with elevated serum homocysteine levels are at an increased risk for early neurological deterioration.10

Life Extension® has long urged members to keep their homocysteine blood levels below 7 to 8 µmol/L whenever possible. This study on acute stroke patients and other recent studies show that homocysteine levels considered “safe” by the medical establishment are quite injurious to the brain, heart, kidneys, and other tissues.120-127

Cerebrovascular Stroke  

What Causes High Homocysteine?

Homocysteine forms in the body from the amino acid methionine.115 Foods such as cereals, legumes, seafood, meat, and dairy products are rich in methionine128 so it is difficult for most people to consistently consume a methionine-deficient diet.

Fortunately, your body has detoxification enzymes that keep homocysteine levels in safe ranges. These homocysteine detoxification enzymes are dependent on the B vitamins, primarily folate, B12, and B6.128-136

Cigarette smoking depletes folic acid in the body, causing smokers to have notoriously high levels of homocysteine.137-139

As we age, our homocysteine detoxification mechanisms become impaired, often resulting in sharply higher homocysteine levels140 in elderly individuals141 that can be accompanied by accelerated atherosclerosis.142

Genetic Defect Causes High Homocysteine

For the majority of people, the proper intake of folic acid, vitamins B12, and B6 and other nutrients will keep their homocysteine levels in safe ranges.

A surprisingly high proportion of Americans,25,143 however, suffer a genetic defect that impairs their ability to convert folic acid into its biologically active form called 5-methyltetrahydrofolate (5-MTHF).144-147

Folic acid itself will not adequately rid the body of excess homocysteine. It needs to be converted to 5-MTHF. The chart on the following page shows the advantage of 5-MTHF over synthetic folic acid.

Fortunately, there is now a high-dose dietary supplement that contains the enzymatically active 5-MTHF form of folate. The advantage of 5-MTHF is that it does not require conversion in the body to slash homocysteine blood levels.147,148 Another plus to 5-MTHF is that it readily crosses the blood-brain barrier to facilitate cognitive function.149

Aging individuals with rising homocysteine levels now have a potent new weapon to reduce their homocysteine level even if they don’t have a defect in their folate-converting genes.

Why Folic Acid Sometimes Fails
Why Folic Acid Sometimes Fails

Homocysteine is reduced in the body by 5-methyltetrahydrofolate (5-MTHF).150

When folic acid is taken, it must go through several enzymatic changes to convert to 5-MTHF.143

A surprising number of people, especially as they age, lack the enzymes needed to convert folic acid into metabolically active 5-MTHF. These individuals need to take a 5-MTHF supplement to directly supply their body with the form of folate that reduces homocysteine.

The chart below shows the many steps required by the body to convert folic acid to 5-MTHF.

Why Folic Acid Sometimes Fails

If one is supplementing with folic acid yet still suffers higher-than-optimal homocysteine, they should add 5 mg (5,000 micrograms) to 10 mg (10,000 micrograms) of 5-MTHF to their daily supplement regimen. This higher potency 5-MTHF supplement is now available without a prescription.


Efficient Way To Determine Who Needs 5-MTHF

There are several variations of genotypes that could hinder one’s ability to convert folic acid into biologically-active 5-methyltetrahydrofolate (5-MTHF).144-147

Rather than pay for these expensive genetic tests, it is far more efficient to have one’s homocysteine blood level tested once a year.

Anyone with a homocysteine reading substantially over 8 µmol/L should take at least one 5,000 micrograms tablet of 5-MTHF daily. Those with homocysteine readings above 12 µmol/L might need to take a 5-MTHF 5,000 micrograms tablet twice daily.

The objective in taking 5-MTHF is to reduce homocysteine levels to optimal safe ranges. If your homocysteine blood test results come back in the low range, then you don’t need to take 5-MTHF.

For optimal homocysteine reduction, adequate amounts of other B vitamins are also required, especially vitamins B2 (50 mg), B6 (75 mg), and B12 (300 micrograms). Sufficient doses of these B vitamins can be found in high-potent multivitamins. In rare cases of B12 absorption problems, vitamin B12 shots (1,000 micrograms) several times a week are needed.

Critical Importance Of Comprehensive Annual Blood Tests

Critical Importance Of Comprehensive Annual Blood Tests  

As you can see on page 6, there are 17 independent risk factors for vascular disease. What this means is that if just one of these markers is out of balance, it can lead to a heart attack or stroke.

The reality for individuals as they age is that they might develop multiple imbalances in their blood such as elevated glucose, LDL, triglycerides, and homocysteine that conspire to sharply increase vascular risks.93,151-153

This is why comprehensive annual blood testing is so critical to protecting against today’s leading killers. Standard blood tests omit the majority of independent vascular risk factors, which explains why arterial disease continues at epidemic levels despite widespread testing for glucose and lipids.

What we have observed in reviewing our members’ blood test results for the past four decades is how quickly a lethal blood marker can elevate over a year’s period of time. For example, it is not unusual for homocysteine levels to spike over a 12-month period as aging wears down detoxification processes.

The good news is that when elevated homocysteine is detected, it can easily be brought down with low-cost 5-methyltetrahydrofolate (5-MTHF).150

Discount Blood Testing

Since the early 1980s, Life Extension® has advised its members to have annual blood tests to identify disease risk factors that can be reversed before serious illness develops.

A barrier some members face is that their conventional doctor still doesn’t recognize the dangers of elevated homocysteine and refuses to test for it. Another problem is that even when doctors order all the blood tests requested, the phlebotomist often fails to check off the appropriate codes on the laboratory requisition form or does not properly draw the blood. When the results come back incomplete, another blood draw becomes necessary, thus inconveniencing the patient.

Even today, most doctors fail to routinely test a patient’s blood for important cardiovascular risk factors such as homocysteine and C-reactive protein. Life Extension® resolved this problem 19 years ago by offering comprehensive blood test panels directly to its members.

Once a year we discount the prices of all our blood tests to a fraction of the price charged by commercial labs. For example, the many tests included in our comprehensive Male or Female Panels can cost around $1,000 at commercial laboratories. Yet members obtain these identical tests during the annual Blood Test Super Sale for only $199.

In addition to the cost savings, members benefit by the convenience of walking into a blood drawing station in their neighborhood, usually without an appointment required. Results come back within a few days and are mailed and/or emailed directly to you. If you have questions about your blood test results, our health advisors are available seven days a week to assist.

Based on what I have discovered as a result of having my blood tested regularly, I am convinced that I have corrected the risk conferred by a number of genetic risk factors that would otherwise have predisposed me to a premature illness or death.

I hope no serious health enthusiast will neglect their annual pilgrimage to a local blood draw station to ensure their homocysteine and other disease risk markers are maintained in optimal safe ranges.

To order a Male or Female Panel, call 1-800-208-3444.

For longer life,

For Longer Life

William Faloon

Male and Female Blood Test Panels

Unlike commercial blood tests that evaluate only a few disease risk factors, Life Extension’s Male and Female Blood Test Panels measure a wide range of blood markers that predispose people to age-related diseases. Just look at the huge number of parameters included in the Male and Female Blood Test Panels:


Lipid Profile

Total Cholesterol
LDL (low-density lipoprotein)
HDL (high-density lipoprotein)

Cardiac Markers

C-Reactive Protein (high sensitivity)


Free and Total Testosterone
Estradiol (an estrogen)
TSH (thyroid function)
Vitamin D (25-hydroxyvitamin D)

Metabolic Profile

Kidney function tests: creatinine, BUN, uric acid, BUN/creatinine ratio
Liver function tests: AST, ALT, LDH, GGT, bilirubin, alkaline phosphatase
Blood minerals: calcium, potassium, phosphorus, sodium, chloride, iron
Blood proteins: albumin, globulin, total protein, albumin/globulin ratio
Hemoglobin A1c (Now Includes HEMOGLOBIN A1c)

Complete Blood Count (CBC)

Red Blood Cell count including: hemoglobin, hematocrit, MCV, MCH, MCHC, RDW
White Blood Cell count including: lymphocytes, monocytes, eosinophils, neutrophils, basophils
Platelet count

Cancer Marker

PSA (Prostate Specific Antigen)

Lipid Profile

Total Cholesterol
LDL (low-density lipoprotein)
HDL (high-density lipoprotein)

Cardiac Markers

C-Reactive Protein (high sensitivity)


Free and Total Testosterone
Estradiol (an estrogen)
TSH (thyroid function)
Vitamin D (25-hydroxyvitamin D)

Metabolic Profile

Kidney function tests: creatinine, BUN, uric acid, BUN/creatinine ratio
Liver function tests: AST, ALT, LDH, GGT, bilirubin, alkaline phosphatase
Blood minerals: calcium, potassium, phosphorus, sodium, chloride, iron
Blood proteins: albumin, globulin, total protein, albumin/globulin ratio
Hemoglobin A1c

Complete Blood Count (CBC)

Red Blood Cell count including: hemoglobin, hematocrit, MCV, MCH, MCHC, RDW
White Blood Cell count including:
lymphocytes, monocytes, eosinophils, neutrophils, basophils
Platelet count

To obtain these comprehensive Male or Female Panels at these low prices, call 1-800-208-3444 to order your requisition forms.

Then—at your convenience—you can visit one of the blood-drawing facilities provided by LabCorp in your area.

Blood testing services are available only in the continental United States and Anchorage, AK.

Not available in Maryland. Restrictions apply for residents of MA, NY, NJ, RI, and PA.


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