Homocysteine (Hcy): Memory Loss, Increased Alzheimer’s, Arterial Disease

Research: Journal of Neurology 2010; 75. Low Vitamin B12 and High Hcy are Markers for Alzheimer’s

271 dementia free people (ages 65-79) were followed for 7 years. B12 is related to Hcy blood levels, and those with low B12 and high Hcy developed Alzheimer’s more frequently.

For every 1 point Hcy increases = 16% increase in Alzheimer’s

So a Hcy of 10 vs 20 = 160% increase in Alzheimer’s

As B12 levels dropped – Alzheimer’s increased

As B12 levels fell, Alzheimer’s increased.  As we age we don’t absorb B12 in the stomach as well.  Absorbing B12 requires stomach acid, which declines as we age. Furthermore, people on Proton Pump Inhibitors like Nexium and Prilosec have very little stomach acid, so there is a much lower absorption of B12 on these medications for GERD.  The acid blockers are some of the most commonly prescribed medications.

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Possible solutions are supplementing with B12 UNDER THE TONGUE, or B12 subcutaneous shots.

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From: Babak Hooshmand, MD, Aging Research Center, Karolinska Institutet, Stockholm,  lead author

Homocysteine is a risk factor for:

Hardening of the arteries – Hcy damages the inside lining of the arteries (endothelium) by increasing oxidative damage (rust), stimulating smooth muscle cells to grow, activating damaging white blood cells to release their toxic contents on the arteries, increasing the stickiness of the blood (activates platelets and clotting factors), which can lead to CLOTS and thus heart attacks and strokes.

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Coronary heart disease (which leads to heart attacks) – lowering  Hcy 25% reduced coronary artery disease 11%.

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Stroke – in 1 study, lowering Hcy 25% reduced stroke risk 90% (The Medical Letter, Oct 27, 2003)

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Abnormal blood clotting (thickened, sticky blood)

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Depression, hostility, and anger – (Life Sci, 2000;66(23):2267).

A lower FOLATE and B12 deficiency is predictive of neuropsychiatric problems in two thirds.

Depressed patients with folate deficiency had higher depression scores, and a poorer response to antidepressants.

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Mood and cognitive functions may be related to methylation processes in the brain. With respect to depression, this  is supported by the similar effect of SAMe to that of folates on mood, and by the influence of folates and SAMe on neurotransmitter metabolism.

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The lowest concentrations of folate and SAMe  in cerebrospinal fluid are found in dementia, including Alzheimer’s disease.  British Medical Journal June 22, 2002;324:1512-1515

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Osteoporosis

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Alzheimer’s and cognitive deterioration – chronic folate deficiency can lead to cerebral (brain) atrophy.

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Concentrations of folate in blood and cerebrospinal fluid decline and those of plasma Hcy rise with age,  contributing to the apparently high incidence of folate (and B12)  deficiency in aging people,

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especially those with psychiatric and cognitive problems.

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Low concentrations of folate in serum, red cells, and cerebrospinal fluid are associated with depression and dementia.

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Multiple sclerosis, motor and gait abnormalities

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Rheumatoid arthritis

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Spontaneous abortion, birth defects, fetal growth retardation – (Nutr Rev 1998 Aug;56(8):236; Eur J Pediatric Surg, 1996 Dec:6 Suppl 1:7-9)

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Preeclampsia (high blood pressure of pregnancy) – (British J of OB Gyn, July 2000;107:935)

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Placental abruption

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Neural tube defects (spina bifida, cleft lip and palate)

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Renal failure

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Type 2 Diabetes – higher INSULIN levels also increase Hcy. Overweight children with high levels of the hormone insulin in their blood are also likely to have high levels of homocysteine. Insulin is a main correlate of homocysteine in obese children and adolescents and suggests that high insulin may contribute to impairment of homocysteine metabolism in childhood obesity. (Diabetes Care 2000;23:1248)

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High cholesterol

What is homocysteine and why is it important? Hcy is an amino acid at the crossroads of an important biological pathway called methylation, which affects a wide range of our biochemistry, thus having far reaching health implications.

Homocysteine is a byproduct in an important biochemical pathway.   Normal genetics for B12, B6, and folate are needed to keep these pathways working well.

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The pathway is called the “METHYLATION” pathway and is like a busy highway interchange in our metabolism.

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Many people – especially of European descent – have problems with “methylation”.   Approximately 30% of Europeans lack strong enzymes that can make these pathways work easily. The result: high homocysteine.

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For example, in TREATMENT RESISTANT DEPRESSION, 50-70% of people have problems with the methylation pathway and Hcy.

The result is they can’t make enough serotonin or dopamine – these neurotransmitters are made by METHYLATION.

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Summary: many health issues are related to this METHYLATION PATHWAY.

High homocysteine MAGNIFIES other risk factors.

Homocysteine plays an important role in depression.

Poor response to antidepressant medication and dysthymia (long term low grade depression) have all been linked to low folic acid levels and high homocysteine levels. Depressed, hostile, or angry people have higher Hcy and higher levels are common among the depressed, with up to 50% of people  >10 μmol/l.

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Anti-depressant medication may be less effective, but it may respond to folic acid. Studies have shown that folic acid replacement, reducing Hcy, is an important treatment for depression. In a 1993 Italian, study of 96 patients, folic acid supplementation improved mood similar to conventional anti-depressants. Several studies have shown that response to prescription anti-depressants like fluoxetine is substantially improved by taking as little as 500 mcg of folic acid per day.

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Elevated Hcy  magnifies the dangers of other risk factors for vascular disease.

In NON-diabetics , an increase of 5 μmol/l increases risk of heart disease just38%,  but the same 5 μmol increase in diabetics raises risk 233% (38% vs. 233%).

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People who smoke have tremendously magnified risk. The European Concerted Action Project showed a 12-fold (1200%!)  risk for cardiovascular disease in smokers > 12 μmol/l.

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High homocysteine with high cholesterol multiplies risk 7 times.

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A particularly lethal combination of risk factors is found when a high homocysteine (>12 μmol/l for females, >15 μmol/l for males) is combined with lipoprotein(a) >40 mg/dl, with risk increased 31-fold.

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The higher your homocysteine, the greater the extent of plaque in the aorta.

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Homocysteine levels of  >20 μmol/l  increase stroke and heart attacks  a startling 10-fold higher over  a level of 9 μmol/l.

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B vitamins are important for the arteries and brain. An MRI study showed that low folic acid was associated with low volumes of brain white matter, the portion of the brain responsible for higher mental function.

Does homocysteine cause heart attacks?

A large body of epidemiologic research shows that the higher your homocysteine level, the greater your risk of heart attack.

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A Norwegian study reported in the New England Journal of Medicine (1997),  followed 587 people with coronary disease, many of whom had undergone bypass surgery or angioplasty. Over 5 years, the mortality rate of those with homocysteine levels < 9 μmol/l was 3.8%.

The mortality rate for those with homocysteine levels of  > 15 μmol  was 24.7%a major difference.

(J Am Coll Cardiol 1996;27(3):517–527)

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Other large studies corroborated these findings.  ( JAMA 2002;288:2015-2022 – Ann Rev Med 1998;49:31-62 )

What causes homocysteine to be elevated?

Any road block in this complex metabolic pathway can elevate homocysteine.

What is normal and what is elevated?

Hcy > 8, risk increases linearly.

ALZHEIMER’S DISEASE – for every increase of 5, Alzheimer’s increases 40%.

Study – NEJM 2002 – 1092 people that were Alzheimer’s free were followed for 8 years.  111 people developed dementia and 83 developed Alzheimer’s.

The HIGHER THE HOMOCYSTEINE THE HIGHER  ALZHEIMER’S  and the worse the COGNITIVE FUNCTION

What may lower homocysteine?

It depends on each individual’s biochemistry, but in general:

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B2 (riboflavin) – helps Hcy escape through a side pathway (trans-sulfuration)

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Folate (B9) – it is important to take “ACTIVE FORMS” of folic acid. Folic acid is the “INACTIVE” form. This is the cheap form that is put in food and most all supplements. If you lack the enzymes (30% of European descent) you will not be able to ACTIVATE folic acid, and this could increase DNA damage.

TOO MUCH “INACTIVE” FOLIC ACID CAN INCREASE SOME CANCERS.

Always look for the ACTIVE forms of folate (like L-5-methy THF) in supplements.

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B12

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TMG (trimethylglycine) – also called BETAINE (Study: TMG in doses of 1.5 grams, 3 grams, or 6 grams DECREASED Hcy 12%, 15%, and 20%) – decreasing Hcy by 12% will reduce CARDIOVASCULAR DISEASE by 5-8% (Gaby – J Clin Nutr 2003)

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Cruciferous vegetables like broccoli, cauliflower, etc.

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Green leafy vegetables

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Peppers

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Vegans may have higher Hcy because enough B12 is only found in animal products

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SAMe

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Methionine, a dietary amino acid,  is needed for normal Hcy (methionine is found in general sources of protein in the diet, meat, seafood, cheese – soy doesn’t contain methionine). RED MEAT has high amounts of METHIONINE which can increase homocysteine. RESTRICTING RED MEAT and MEAT may lower homocysteine. (see discussion below on limiting METHIONINE for vascular health)

Methionine is converted in vivo (in the body) to homocysteine, which in turn has negative effects on endothelial function and structure. Particularly it degrades collagen, elastin and the proteoglycans in arteries.

Protein deficiency (some vegans) can lead to higher Hcy – B12 is found in meats

DISCUSSION OF METHIONINE AND HOMOCYSTEINE

Here is a good passage from this paper: http://www.pnas.org/content/100/25/15089.full

Whether excess of dietary methionine intake in humans is atherogenic remains to be determined; however, considerable evidence from animal experiments suggests that these findings are not limited to the ApoE-deficient mouse model. A similar experimental dissociation of hyperhomocysteinemia and atherosclerosis has been observed in pigs and primates fed atherogenic diets (21, 59). Ambrosi et al. (21) showed that feeding pigs a methionine-rich diet for 4 months induced hyperhomocysteinemia and atherosclerosis. Folate supplementation of the methionine-rich diet successfully normalized plasma homocysteine levels but did not reduce methionine-induced vascular lesions. Similarly, when Lentz et al. (59) fed cynomolgus monkeys a high-fat and -cholesterol diet for 13-26 months, it induced not only hypercholesterolemia and atherosclerosis, but also hyperhomocysteinemia and B vitamin deficiency. When the same diet was supplemented with folic acid, vitamin B12, and vitamin B6, blood vitamin and homocysteine levels were normalized, but no attenuation of atherosclerosis or vascular dysfunction occurred in supplemented monkeys (59).

It is difficult to reconcile these data with the observation that rare congenital defects in homocysteine metabolism are associated with premature thrombotic and arteriosclerotic disease, whether the defects are in genes of the transsulfuration pathway (which are associated with elevated methionine) or of the methylation pathway (which are associated with low methionine) (20). This observation has often been cited as key evidence supporting the view that vascular disease in hyperhomocysteinemia and particularly atherosclerosis is due to homocysteine per se rather than an effect of its metabolic determinants. Nevertheless, attempts to mimic these human conditions in knockout mice that are defective in transsulfuration or in the remethylation of homocysteine have so far not induced either arteriosclerosis or atherosclerosis in these models despite achieving hyperhomocysteinemia (26, 60). This finding leaves unanswered which aspects of vascular pathology might be causally linked to homocysteine or whether additional factors might be necessary for the putative vasotoxic properties of homocysteine to become apparent (10, 11).

Although the role of homocysteine in atherosclerosis remains to be determined (10, 11), the atherogenic potency of excess methionine intake is a well documented, if often overlooked, phenomenon. Abundant data on dietary amino acid imbalances describe “methionine toxicity” that leads to growth retardation and histopathologic changes in liver, kidney, and spleen, at methionine intake as low as 2% of diet (61). Numerous studies show high methionine intake to produce atherosclerotic changes in mice (15, 16) rats (17, 18, 62-64), rabbits (19, 65), and pigs (21, 22), even if the results have often been attributed to a coincident rise in plasma homocysteine. Further evidence of methionine’s vascular toxicity can be derived from studies that examine the vascular effect of dietary protein content and composition. For example, high methionine casein based diets promote vascular pathology in ApoE-deficient mice to a greater extent than low methionine isoflavone-free soy-protein-based diets even within the range of normal dietary methionine intake and similar total protein content (66). Together, these observations demonstrate that methionine toxicity is not limited to the ApoE-deficient mouse model. Additional studies are needed to determine the mechanism that underlies this atherogenic property of excess dietary methionine and whether this mechanism could at least in part explain the epidemiological association between elevated homocysteine levels and cardiovascular disease.

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For educational purposes only. Consult your physician for any health issues or treatment decisions.

*These statements have not been evaluated by the Food & Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.