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December 2003

Elevated Homocysteine Raises Risk of Stroke, Dementia
Protecting Your Brain and Heart Through Folic Acid and B Vitamin Supplementation

By Carmia Borek, Ph. D.

The most common form of senility is Alzheimer’s disease, which accounts for more than 70% of all dementia cases. People with cardiovascular risk factors and a history of strokes have an increased risk of both vascular (arteriosclerotic) dementia and Alzheimer’s disease.

Elevated plasma homocysteine (hyperhomocysteinemia) is now recognized as a strong, independent risk factor for stroke and dementia.
Hyperhomocysteinemia is caused by deficiencies in vitamins B6, B12 and folic acid.1 The adverse vascular and neurotoxic effects of homocysteine are associated with excess free radical generation (oxidative stress).2

Elevated plasma homocysteine, however, is a reversible risk factor. Consumption of foods containing B vitamins and supplementation with folic acid and vitamins B6 and B12 are the primary preventive and therapeutic treatments. The intake of antioxidants through diet and supplements protects against oxidant stress and helps maintain the normal function of the vascular system and brain.1,3

Elevated Homocysteine—Potentially Lethal
Homocysteine is a toxic, sulfur-containing amino acid formed from the amino acid methionine. Under normal metabolic conditions, homocysteine is removed from the circulatory system by recycling back to methionine, in a chemical reaction (re-methylation) that requires folate and vitamin B12. Another means of homocysteine disposal is its conversion (transsulforation) to the amino acid cysteine, in a reaction that requires vitamin B6.

In hyperhomocysteinemia, homocysteine levels can range from 14 micromoles/liter all the way up to 100 micromoles/liter in severe cases.1 Genetic factors such as mutations in genes that regulate folate and vitamin B6 metabolism, as well as severe renal disease, increase homocysteine levels.

Elevated homocysteine damages endothelial cells that line blood vessels and induces thrombosis that can lead to heart attacks and stroke. Homocysteine produces breaks in DNA and induces apoptosis (a programmed cell suicide) that is a major cause of neuronal death in dementia.4

An increase in homocysteine affects multiple organs during aging. Humans with inherited defects in enzymes involved in homocysteine detoxification show features of accelerated aging and a marked propensity for age-related diseases.

Homocysteine, B Vitamins Closely Linked
Recent studies in the UK and Norway of people 65 years and older and of young people ages 4 to 18 found that plasma homocysteine levels increase progressively with age and are directly related to plasma levels of folate and vitamins B12 and B6. The lower the B vitamin levels, the higher was the homocysteine concentrations.5

Along the same lines, a high intake of vitamins B6 and B12 along with folic acid substantially lowers homocysteine, as reported recently by Dr. den Heijer at the XIX Congress of the International Society on Thrombosis and Haemostasis, held in July 2003 in the UK. In a randomized study, 353 patients received high daily doses of folic acid (5 mg), vitamin B6 (50 mg), and vitamin B12 (0.4 mcg), while 353 patients received a placebo. Three months later, the vitamin-supplemented group had a 30-40% decrease in homocysteine levels, compared to patients on placebo. The results emphasize the importance of B vitamin supplementation to offset age-related declines in vitamin levels and counteract age-related increases in homocysteine.

High Homocysteine Implicated in Dementia
The association between high levels of homocysteine and dementia—including Alzheimer’s disease—has been observed in epidemiological studies and confirmed in case-control studies in which patients with vascular dementia and Alzheimer’s disease had higher levels of homocysteine than did healthy people.6

A direct link between increases in plasma homocysteine and loss of cognition was shown by Seshardi et al at the Boston University School of Medicine and reported in the New England Journal of Medicine (Feb. 14, 2002). The study, part of the ongoing Framingham Heart Study, provides compelling evidence that in adults with intact cognition, an elevation in plasma homocysteine over time is associated with an increased incidence of dementia, including Alzheimer’s disease. The results also underscore the importance of B vitamin supplementation for preventing homocysteine-associated dementia.1

The study enrolled 1,092 elderly subjects without dementia (667 women and 425 men), with a mean age of 76 years. Over a median follow-up period of eight years, dementia (including vascular dementia and other types of non-Alzheimer’s dementia) developed in 111 subjects (10.2%; 74 women and 37 men), and 83 of these subjects (62 women and 21 men) were diagnosed with Alzheimer’s disease. Hyperhomocysteinemia (plasma homocysteine higher than the baseline of 14 micromoles per liter) doubled the risk of dementia or Alzheimer’s disease in the subjects with the highest levels of homocysteine. An estimated 16% of the observed incidences of Alzheimer’s disease were attributable to hyperhomocysteinemia.

Increases in homocysteine levels occurred well before the onset of clinical signs of dementia, and there was a strong association between homocysteine levels and risk; that is, an increment increase of 5 micromoles per liter of homocysteine raised the risk of Alzheimer’s disease by 40%.

The study’s authors also found that the homocysteine-related doubling of risk of dementia was of the same magnitude as the increased risk of death from cardiovascular disease and stroke (a twofold increase) seen in earlier studies.

The study concluded that “An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer’s disease” and that “vitamin therapy with folic acid, alone or in combination with vitamins B6 and B12 and dietary supplementation with enriched-grain products and breakfast cereal containing folate can reduce plasma homocysteine levels.”1

A recent study in Australia examined the brains of 36 healthy seniors and found that those with high homocysteine levels were twice as likely to show a loss of brain cells compared to those with normal homocysteine levels.7

Another study, from Queens University in Belfast, Northern Ireland, published in Stroke in October 2002, found that moderately high levels of homocysteine were associated with significant increases in the risk of Alzheimer’s disease, vascular dementia, and stroke, compared with people with lower levels of homocysteine. Increases in homocysteine were not related to any genetic defect that affects folate metabolism and raises homocysteine. The study concluded that since B vitamins and folate-fortified foods can reduce homocysteine levels, B-vitamin supplementation may be appropriate for most adults, and that the study results warrant a placebo-controlled study of folate and vitamins B6 and B12 in people who are at risk for stroke and dementia.8 An accompanying editorial advised that because people differ in their dietary habits, supplementation with 2000-5000 mcg of folic acid daily and a similarly safe dose of vitamin B12 may be appropriate.

How Hyperhomocysteinemia Leads to Dementia
Numerous studies offer clues as to the various ways in which high levels of homocysteine induce the vascular and neuronal damage implicated in the development of dementia.

Vascular effects. The Nun study of aging and Alzheimer’s disease dementia found a worsening of dementia when areas of dead tissue (infarcts) were present in the brain, indicating that homocysteine contributes to dementia by inducing vascular changes that result in insufficient blood flow to the brain and cell death.9

DNA damage and cell death. Other events contribute to neuronal cell death by homocysteine. Experiments in cell cultures show that homocysteine can directly kill neurons of the hippocampus, the area of the brain associated with memory. Cell death was induced by oxidative stress, DNA damage, and apoptosis.10 Such events occurring in vivo would result in a deficit in cholinergic neurons and faulty transmission of signals in the brain that characterize dementia.

Folate deficiency and loss of DNA repair. Homocysteine’s damaging effects on DNA are worsened by folate deficiency. Studies show that a lack of folate prevents the repair of DNA in hippocampus neurons following exposure to homocysteine, resulting in the accumulation of DNA damage and cell death. Investigators from the Laboratory of Neuroscience at the National Institute on Aging in Baltimore, MD, found that a lack of folic acid rendered hippocampus neurons vulnerable to death by amyloid beta peptide, a free radical producing toxic molecule found in the brains of Alzheimer’s disease patients. Thus, folate deficiency increases the toxicity of amyloid beta peptide, and when occurring in vivo, could lead to accelerated neuronal cell death and dementia.11 This was seen in experimental mice that were genetically modified to have high levels of amyloid beta peptide and kept on a folic acid-deficient diet. The mice showed increased DNA damage and neurodegeneration in the hippocampus, further demonstrating that folic acid deficiency sensitizes cells to oxidative damage induced by amyloid beta peptide.11