Brain twisters – The missing pieces of the Alzheimer’s puzzle

Several years ago, the news media reported that “huge doses of an ordinary vitamin appeared to eliminate memory problems in mice with the rodent equivalent of Alzheimer’s disease”. Researchers at the University of California at Irvine had given the human dose equivalent of 2,000–3,000 mg of vitamin B3 to mice with Alzheimer’s disease.1 It worked. As Kim Green, one of the study’s authors, described it: “Cognitively, they were cured. They performed as if they’d never developed the disease.”

Reporting on the findings, The Irish Times newspaper concluded: “Healthy mice fed the vitamins also outperformed mice on a normal diet,” and quoted study co-author Frank LaFerla as saying: “This suggests that not only is it good for Alzheimer’s disease, but if normal people take it, some aspects of their memory might improve.”2 “If we combine this with other things already out there,” added Green, “we’d probably see a large effect.”

The study had specifically employed nicotinamide, the form of vitamin B3 found in meat, poultry, fish, nuts and seeds. Nicotinamide is also the form of niacin used in a great quantity in dietary supplements and is more commonly known as ‘niacinamide’.

In response to this promise of a breakthrough, the media were quick to warn that “scientists aren’t ready to recommend that people try the vitamin on their own outside of normal doses”.3 In other words, extra large amounts of a vitamin are helpful – but don’t take them.

In the UK, the British Broadcasting Corporation (BBC) quoted Rebecca Wood, chief executive of the Alzheimer’s Research Trust, who said, “Until the human research is completed, people should not start taking the supplement . . . People should be wary about changing their diet or taking supplements. In high doses vitamin B3 can be toxic.”4

By the time The Irish Times had finished their take on the story, it had turned from a health breakthrough to a serious health concern: “People have been cautioned about rushing out to buy high-dose vitamin B3 supplements in an attempt to prevent memory loss . . . The warnings came together one day [after the announcement] . . . Vitamins in high doses can be toxic.”2

The choice of words makes for pithy headlines, but is hardly accurate. As the late Canadian biochemist and psychiatrist Abram Hoffer, one of the pioneers of orthomolecular medicine (high-dose vitamin therapy), coolly noted: “There have been no deaths from niacin supplements.”

The most common side-effect of niacinamide at very high doses is nausea, but this can be eliminated by taking less niacinamide, or by taking regular niacin instead, which may cause a warm flush, or inositol hexanicotinate, which does not. All are forms of vitamin B3.

The LD50 (lethal dose that would kill half of those taking it) for dogs is 5,000–6,000 mg per kg of body weight. “That is equivalent to almost a pound of niacin per day for a human,” said Hoffer. “No human takes 375,000 mg of niacin a day. They would be nauseous long before reaching a harmful dose.”

Dr Hoffer should know. He conducted the first double-blind, placebo-controlled, clinical trials of niacin, which showed that
it’s not toxic to the liver. “Niacin therapy increases liver function
[test results],” he said. “But this elevation means that the liver is active. It does not indicate an underlying liver pathology.”

The medical literature repeatedly confirms niacin’s safety. For over 50 years, integrative physicians have used vitamin B3 in doses as high as tens of thousands of milligrams (mg) per day. Cardiologists frequently give patients thousands of mg of niacin daily to lower cholesterol, and niacin is preferred because its safety margin is so wide. The American Association of Poison Control Centers’ (AAPCC) Toxic Exposure Surveillance System (TESS) annual reports indicate not even one death per year due to niacin in any of its forms.5

Orthomolecular physicians have also found that niacin and ‘nerve’ disorders of all varieties go together, with niacin and other nutrients an effective treatment for obsessive–compulsive disorder, anxiety, bipolar disorder, depression, psychotic behavior and schizophrenia.

New research confirms that niacinamide (the same form of B3 used in the Alzheimer’s research) “profoundly prevents the degeneration of demyelinated axons and improves the behavioral deficits” in animals with an illness similar to multiple sclerosis.6

According to Hoffer, “There appears to be a statistically significant link between a low dietary intake of niacin and a high risk of developing Alzheimer’s disease. A study of the niacin intake of 6,158 Chicago residents 65 years of age or older established that the lower the daily intake of niacin, the greater the risk of becoming an Alzheimer’s disease patient.” The group with the highest daily intake of niacin had a 70 percent decrease in incidence of this disease compared with the lowest intake group.7

An early signal

Hoffer died a few years ago, convinced that the key to Alzheimer’s lay in taking preventative dietary measures. “If everyone started on a good nutritional program supplemented with optimum doses of vitamins and minerals before age 50, and remained on it, the incidence of Alzheimer’s disease would drop precipitously,” he said.

There’s a good reason why levels of niacin are so important to prevent Alzheimer’s, and it has do with a little-known protein called homocysteine.

Homocysteine is a toxic amino acid and high levels make people more prone to injury of the cells lining blood vessels, causing thickening and narrowing of arteries – both those in the heart and those in the brain (see box, above). Raised homocysteine levels also reflect faulty methylation (a process that replaces hydrogen atoms with three hydrogen atoms bonded to a carbon atom), which is required for making neurotransmitters and phospholipids. Homocysteine also damages blood vessels by potentially impairing oxygen and nutrient flow to the brain, a situation associated with vascular dementia, and induces neurotoxicity by activating receptors of the amino acid N-methyl-d-aspartate (NMDA) and increasing so-called oxidative stress, an imbalance between the production of cell-damaging free radicals and the body’s ability to neutralize their actions with antioxidants.

Lowering homocysteine has potentially many positive effects on brain function, including reducing this oxidative stress (see box, page 31).

The evidence for a connection between homocysteine and Alzheimer’s disease is mounting. Reviews of the data reveal that high blood levels of homocysteine and low blood levels of folic acid and cobalamin (vitamin B12) are, in fact, early markers of the development of the condition.8

According to another review of the evidence: “Seventy-seven cross-sectional studies on more than 34,000 subjects and 33 prospective studies on more than 12,000 subjects have shown associations between cognitive deficit or dementia and homocysteine and/or B vitamins.”9 And high homocysteine levels even seem to correlate with a person’s rate of cognitive decline,10 as do low levels of B12.11

This and other research offer ample evidence that lowering homocysteine by giving appropriate doses of nutrients, including vitamin B6, vitamin B12 and folic acid, can reduce your risk of Alzheimer’s disease.

But at what point in the process is cognitive decline reversible, and what dosage of nutrients offers maximum protection?

Just this question was addressed by a clutch of Dutch researchers from Wageningen University, who gave folic acid supplements (0.8 mg/day) or a placebo for three years to a group of adult volunteers over 50 with raised homocysteine levels but no evidence yet of cognitive decline. Those in the treatment group experienced highly significant improvements in memory, information-processing speed and sensorimotor sp
eed (the speed of movement after a triggering sensation).12

In another study, Oxford University researchers assembled a group of volunteers with mild cognitive impairment, after measuring their cognitive function and degree of brain shrinkage on magnetic resonance imaging (MRI) scans. Homocysteine levels above 9.5 micromoles per liter (µmol/L) were linked with accelerated brain shrinkage and cognitive decline, and these greater rates of brain shrinkage were, in turn, linked with lower final cognitive test scores (see box on page 26 for how to test for homocysteine levels).13

Nevertheless, when these volunteers were given folic acid (0.8 mg/day), vitamin B12 (0.5 mg/day) and vitamin B6 (20 mg/day), they all experienced significant reductions in the rate of brain atrophy. And the worse off the patients were in terms of homocysteine, the greater the improvement in terms of slowed brain shrinkage; patients with baseline homocysteine levels greater than 13 µmol/L had rates of atrophy that were 53 percent lower than other patients in the treatment group.13

An independent evaluation of these patients showed that those starting out with a higher baseline homocysteine enjoyed a greater decrease in deterioration of cognitive function, with no significant further decline (de Jager CA, 2011; unpublished data).

But what happens to patients who already have Alzheimer’s disease? Other researchers from mutiple medical centers scattered across the US tried giving B vitamins to people already diagnosed with mild-to-moderate Alzheimer’s disease, including folic acid (5 mg/day), vitamin B6 (25 mg/day) and vitamin B12 (1 mg/day), over a period of 18 months. Those with milder Alzheimer’s disease taking the B vitamins had significant responses and barely got worse over 15 months, while those taking the placebo showed steady decline. The B-vitamin patients also experienced significant drops in homocysteine levels from an average of 9.1 µmol/L to 6.8 µmol/L.14

B vitamins also seem to help vascular dementia, the second most common form of dementia, caused by problems in the supply of blood to the brain, as shown by a study from the Chinese University of Hong Kong in Shatin. When volunteers with mild-to-moderate Alzheimer’s disease or vascular dementia with homocysteine levels over 13 µmol/L were given vitamin B12 (1 mg/day) and folic acid (5 mg/day) for two years, they experienced significantly less cognitive decline when measured by a neuropsychological test called the Mattis Dementia Rating Scale.15

These studies suggest that taking homocysteine-lowering B vitamins at the very least can arrest mental decline and possibly improve it in people over age 50 with raised homocysteine levels (more than 9.5 µmol/L), even where there’s already evidence of such decline; it may even stop or slow cognitive decline in those with mild Alzheimer’s. However, further research is needed to determine whether these improvements can truly prevent the development of full-blown Alzheimer’s disease, and what combination and intake of homocysteine-lowering nutrients would have the most significant clinical effects.16

Other helpful nutrients

Besides these studies, a cluster of general practitioners have been experimenting with adding supplements like N-acetylcysteine (NAC) to B vitamins (see box, page 31) to manage patients with high levels of homocysteine and cognitive decline. Dr Andrew McCaddon, of Wales College of Medicine in Wrexham, UK, reported on his positive experience with seven patients, one of whom had undergone full radiological assessments before and after treatment. After giving the patients high-dose B vitamins with NAC, Dr McCaddon found significant “clinical efficacy.”17

There are good reasons for giving these supplements. Homocysteine is processed in the liver by the betaine–homocysteine methyltransferase (BHMT) pathway, which requires trimethylglycine (TMG; another name for betaine) and zinc, both of which help to break down homocysteine, so reducing its accumulation. Adding NAC, TMG and zinc to the B-vitamin combo may bring about further clinical improvements, although this has yet to be tested in a clinical trial.

Preliminary evidence also points to the protective role of vitamins C and E in keeping your brain sharp. One study of 4,740 elderly (age 65 and over) residents of Cache County, Utah, who were taking both C and E, found a 64 percent reduction in the number of cases of Alzheimer’s disease among them. The lowest risk was reported in those supplementing with at least 1,000 mg a day of vitamin C with at least 1,000 international units (IU) a day of vitamin E.18

Such benefits, though, don’t seem to be enjoyed by those taking vitamin E alone; one study showed no benefit in patients taking 2,000 IU/day of the vitamin compared with those taking the common Alzheimer’s drug donepezil (Aricept) or a placebo.19

Besides supplements, eating the right essential fatty acids (EFAs) can have a profound effect on the risk of developing dementia. Eating fish once a week reduces the risk of Alzheimer’s disease by 60 percent, according to one study. Researchers at the Rush-Presbyterian-St Luke’s Medical Center in Chicago, Illinois, following 815 people 65 to 94 years old, discovered that a low dietary intake of fish or omega-3 fatty acids was strongly linked to Alzheimer’s disease risk, with the strongest link being the amount of docosahexaenoic acid (DHA) in the diet. The higher the intake of DHA, the lower the risk of developing Alzheimer’s, although patients had to take at least 100 mg/day to see any benefit.20

This fits with the findings of another randomized double-blind, placebo-controlled trial showing that taking 900 mg/day of DHA for 24 weeks improved learning and memory among those with age-related cognitive decline.21

There may be an explanation for why we have yet to see strong evidence of complete reversal of disease with B vitamins. A long-standing nutrient deficiency can lead to nutrient dependency – an exaggerated need for the missing nutrient – that cannot be met by dietary intakes or even low-dose supplementation. Robert P. Heaney, MD, uses the term ‘long-latency deficiency disease’ to describe conditions that fit this description.22

There’s already a pathology that requires unusually large quantities of vitamins to repair damaged tissue. Thirty-five years ago, Hoffer wrote: “The borderline between vitamin deficiency and vitamin dependency conditions is merely a quantitative one when one considers prevention and cure.”23

The US Alzheimer’s Association’s Dr Ralph Nixon has said that previous research has suggested that vitamins such as E, C and B12 may help people lower their risk of developing Alzheimer’s. On their website (although you have to search for it), the Alzheimer’s Association says, “Vitamins may be helpful. There is some indication that vitamins such as vitamin E, or vitamins E and C together, vitamin B12, and folate may be important in lowering your risk of developing Alzheimer’s.” But in general, the Alzheimer’s Association website (www.alz.org) has strikingly little to say about vitamins, while it hastens to tell people: “No one should use vitamin E to treat Alzheimer’s disease except under the supervision of a physician.”

There’s no doubt that memory loss and an increased risk of Alzheimer’s disease are strongly associated with low levels of vitamin B12 and folic acid, fish consumption and raised blood levels of homocysteine. In those with early-stage Alzheimer’s disease, there is evidence of a reduction in cognitive decline with high-dose B vitamins. The need for early screening for cognitive decline and high homocysteine is essential, given the growing body of evidence that homocysteine-lowering nutrients can arrest cognitive decline and accelerate brain shrinkage.

A measure of journalistic caution is understandable, especially given the ever-new promises made for pharmaceutical products. Yet the drugs routinely used to treat Alzheimer’s d
isease have had a disappointing, even dismal, success rate. Over five million Americans now have Alzheimer’s, and that number is estimated to reach 14 million by 2050. Potentially, nine million.

How high homocysteine levels damage your brain

When homocysteine builds up in the blood, it forms homocysteine thiolactone, made in the liver by an enzyme that participates in protein formation and other processes. The buildup of homocysteine thiolactone causes blood platelets to aggregate or clump together while increasing intakes of low-density lipoprotein (LDL) by macrophages, leading to fatty deposits (arterial plaques) in artery walls in the form of ‘foam cells,’ which release fat and cholesterol into many arteries, including those feeding the brain.

Homocysteine thiolactone is also released into other cells surrounding arterial walls, affecting the way those cells handle oxygen.

As a result, highly reactive free radicals accumulate within cells, damaging the lining of blood vessels and causing blood clots to form, while stimulating the growth of cells that form fibrous and degenerative elastic tissue in the arteries.

Homocysteine is a necessary part of the methionine cycle, which is controlled by vitamin B12 and folic acid. Whether or not your homocysteine levels rise depends upon the total methionine (an essential amino acid) content of your diet – most people get enough from high-protein animal-based foods like seafood, meat and dairy – and the amount of vitamin B6, B12 and folic acid consumed.

How to test for homocysteine

Laboratories can test your homocysteine level by taking a simple blood sample via a needle in a vein in one arm. This sulfur-containing amino acid, normally present in very small amounts in all cells of the body, is a product of methionine metabolism, one of the 11 essential amino acids required by the body from diet.

If you’re healthy, the homocysteine in your cells is quickly converted to other elements required by the body. If not, it accumulates, causing hardened arteries, by damaging blood vessel walls all over your body, including your brain. High levels are considered anything over 9.5 µmol/L of your blood, which can be treated by following a supplement program rich in B vitamins and other nutrients (see box, page 28).

Many laboratories offer homocysteine testing, including Quest Diagnostics (www.questdiagnostics.com). There are also online services, such as Integrative Psychiatry (www.integrativepsychiatry.net) that provide the lab order for a blood draw at a local lab.

What to do if you have a high homocysteine
level

If your homocysteine result is above 9.5 µmol/L, there is an increasing body of evidence that now links such high levels to metabolic syndrome (blood-fat/blood-sugar disorders), insulin resistance, diabetes and a higher risk of dementia/Alzheimer’s disease.

Here’s what you can do to lower your levels.

Follow a low-glycemic (low-sugar) diet that is high in oily fish, nuts, seeds and beans, with plenty of antioxidant-rich fruits and vegetables.

Limit or avoid coffee, which is known to raise homocysteine levels (although whether or not coffee increases or reduces the risk of Alzheimer’s is currently inconclusive).

Supplement with the following homocysteine-lowering nutrients daily:

•folic acid (400–800 mg)

•vitamin B6 (20–40 mg)

•vitamin B12 (0.5–1 mg, preferably as methylcobalamin)

Try adding these other nutrients every day:

• N-acetylcysteine, or NAC (500–1,000 mg)

•omega-3 essential fatty acids (fish oil containing 500–1,000 mg of DHA)

•Trimethylglycine, or TMG (1,000–2,000 mg)

•zinc (10–15 mg)

•vitamin E (1,000 IU)

•vitamin C (1,000+ mg)
or more).

B vitamins for a bigger brain

When volunteers with mild cognitive impairment were given B vitamins, they experienced significant reductions in brain atrophy (shrinkage). Those patients with baseline homocysteine levels greater than 13 µmol/L had rates of atrophy 53 percent lower than other patients.

Bs for dementia

People with mild Alzheimer’s disease taking B vitamins barely got worse over 15 months, while those taking a placebo showed steady decline.

The B vitamin patients also experienced significant drops in homocysteine levels from an average of 9.1 µmol/L to 6.8 µmol/L.

C and E for prevention

Elderly people taking supplements of vitamins C and E are 64 percent less likely to suffer from Alzheimer’s disease, according to a US study. The lowest risk was reported in those supplementing with at least 1,000 mg/day of vitamin C and 1,000 IU/day of vitamin E.

How supplements stop homocysteine from damaging the brain

The methionine cycle needs vitamin B12 and folic acid to function properly. In this cycle, methionine is converted into S-adenosyl methionine (SAMe), a methyl donor involved in numerous biological reactions in a process known as methylation, where a methyl group (three hydrogen atoms bound to a carbon atom) is transferred to a molecule like homocysteine, thereby lowering levels of homocysteine and preventing heart disease.

SAMe synthesis is hampered by oxidative stress, when the body’s antioxidant capacity is overwhelmed by the production of free radicals, unstable molecules that cause cell damage. Vitamin B12 itself is also vulnerable to oxidative damage; oxidative stress increases the need for SAMe while decreasing its synthesis. Homocysteine is essential for glutathione levels in liver cells.

According to Dr Mark Hyman, who calls glutathione ‘the mother of all antioxidants,’ its levels are depleted by stress, pollution, toxins and trauma, making you vulnerable to more oxidative stress, infections, free radicals and even cancer.1

This suggests that, by supplementing with glutathione, or its precursor N-acetylcysteine (NAC), together with B12, SAMe can be spared and homocysteine levels lowered.

Main article

How supplements stop homocysteine from damaging the brain