by George J. Brewer, MD, and John D. MacArthur
The average lifespans of people in so-called developed countries have gradually increased over the last 100 years. This can be attributed largely to factors reducing mortality from infectious diseases, including improved sanitation, immunizations, and antibiotics. This is the good news. The bad news is that an increasing proportion of our elderly people are losing their golden years to dementia from Alzheimer’s disease (AD). This begins with memory loss and progresses with the loss of thinking capability until patients can’t function by themselves. The prevalence of AD in our aging population is frightening, affecting 10% of those over age 60, 20% of those over age 70, and 30% of those over age 80.1 There are roughly 5 to 6 million AD patients in the US and an equal number of people with mild cognitive impairment (MCI), memory loss, but not enough loss of function to be called AD. In general, MCI is a precursor to AD, with 80% eventually developing AD, at the rate of 15% per year.
Amyloid-Beta and the Pathogenesis of AD
Amyloid-beta is a small piece of protein clipped off a larger protein by an enzyme called beta secretase. AD is characterized by large plaques (or particles) in the brain that are composed primarily of amyloid-beta. These plaques, plus another brain pathology called neurofibrillary tangles, are the characteristic findings in the AD brain that allow the pathologist to make the diagnosis of AD at autopsy. While autopsy is the only way to definitively make that diagnosis of AD, clinicians have now become so good at making the diagnosis that 95% of the time or more, the diagnosis of AD in living patients is confirmed at autopsy.
The amyloid plaques are so intimately involved with AD that most scientists have long thought they are the principal cause of brain damage and cognition loss.2 It is known that there is increased damage from oxidant radicals in the AD brain, and amyloid plaques are a strong source of oxidant radicals, particularly when they bind copper or iron.3
Two Interesting Facts About Our Current Epidemic of AD
One interesting fact is that AD was unknown prior to the 20th century. The first case was published in 1907 by German psychiatrist and neuropathologist Alois Alzheimer, which led to the disease being called by his name.4 Why is a disease that became so prevalent in the latter part of the 20th century apparently absent in the 19th century? Some say that it was there back then, just not recognized as a disease. Waldman and Lamb examined this question.5 They reviewed the extensive writings of Osler, an internist, and Gowers, a neurologist, during the latter part of the 19th century, and found no mention of an AD-like disease.6,7 More important, the textbook of pathology written by Boyd during that period and updated until 1938 made no mention of amyloid plaques and neurofibrillary tangles in brains at autopsy.8 The failure to observe AD, particularly the failure of it to show up in brain pathology at autopsy makes it unlikely that AD was present in any significant frequency in the latter part of the 19th century.
Another common explanation is that since AD is a disease of aging, there were not enough old people in the 19th century to show a significant prevalence. Waldman and Lamb showed that in 1911, half the population of France was living to age 60, the age now when high prevalence of AD begins.5 US census figures for 1900 show that 3.2 million people were over 60 years of age. At today’s prevalence, there would have been 36,300 US cases of AD – plentiful enough to have been present in clinics and particularly to have shown up at autopsy.
A second interesting fact is that this epidemic is primarily hitting developed countries. So-called developing countries, such as those in Africa, South America, and much of Asia, are not sharing in this major increase in prevalence.9 Japan, a developed country with a low prevalence, is a unique exception that we will discuss later.
Together, these facts lead to an inescapable conclusion. Something introduced into the environment in developed countries, but not developing countries, in the last 100 years has caused the epidemic. Waldman and Lamb believed that a major environmental causative change was meat eating. We agree with Grant that a high-fat diet is one causative factor in AD, and the high-fat diet comes with meat eating and other changes in the Western diet.10 Although meat consumption is rising in developing countries, the per capita consumption of meat is still nearly four times higher in industrialized countries. (It was six times higher in the 1960s.)11
Inorganic Copper Toxicity as a Major Factor in the AD Epidemic
Scientists these days like to talk about the complexity of AD. They formulate drugs or agents designed to lessen the amyloid-beta burden in the brain or to attack biochemical aspects of the neurofibrillary tangles. One of us (GJB) has long suggested there is a simpler line of attack: prevent AD by eliminating ingestion of inorganic copper.12-20 This concept, however, has yet to enter the conversation of the scientific community.21 In one review, the authors rejected the hypothesis by saying that it was unlikely that something as simple as a dietary ingredient could explain a disease as complex as AD. These authors did not read the papers carefully. It is not simply dietary copper ingestion that is involved, but the ingestion of inorganic copper. Organic copper is food copper. It is tightly bound to food proteins, is metabolized by the liver, and is safe. Inorganic copper is a simple salt of copper, the kind put in nutritional supplements or leached into drinking water. Some of this inorganic copper bypasses the liver and adds directly to the “free copper” pool of the blood, and is unsafe.
The epidemic of AD took off after 1950, about the time that the use of copper plumbing in developed countries became widespread. It is our belief that the leaching of copper from copper plumbing into the drinking water is a major causal factor in the AD epidemic. Let’s examine the evidence.
An epiphany in our thinking about this occurred in 2003 with research published by Sparks and Schreurs.22 They found that addition of as little as 0.12 ppm copper to the distilled drinking water in the rabbit model of AD greatly enhanced both the AD-type brain pathology and impaired the cognitive abilities of the animals. In their 2006 follow-up study, when they added copper to the drinking water of beagles and mice, it produced significantly enhanced brain levels of amyloid-beta in these animals, too. Their research data “suggest that water quality may have a significant influence on disease progression and amyloid-beta neuropathology in Alzheimer’s disease.”23
Their work was replicated in 2007 by Deane and Zlokovic, who compared mice that drank distilled water to mice that drank water containing 0.12 ppm of copper. The copper-consuming mice had one-third more amyloid-beta in their brains and about twice as much copper in the cells lining the blood vessels of their brains than did the mice that drank distilled water. They also had one-third fewer LRP molecules in those blood vessels. The brain can remove amyloid-beta, thanks to a molecule called LRP (low-density lipoprotein receptor-related protein) that escorts it out of the brain and into the body for elimination. Using human cells, the research team discovered that copper damages LRP to such an extent that it stops working.24 For reference, the US EPA allows 1.3 ppm copper in human drinking water, over 10 times the amount found toxic in animal AD models.
Regarding the brain toxicity of inorganic copper in supplement pills, Morris et al. have shown in a population study that those in the highest quintile of copper intake (and whose diets were high in saturated and trans fats) lost cognition at six times the rate of other groups.25 There was “a strong dose-response association with higher copper dose in vitamin supplements” and cognitive decline in the high-fat group.
Current data show that the percentage of the US population who take at least one multivitamin/multimineral product increased from 30% in 1988 to 39% in 2006.26 Most of these supplements contain copper.
One of us (GJB) has had considerable experiences with copper through work on Wilson’s disease (WD), an inherited disease of copper accumulation and copper toxicity.27 We developed zinc as a treatment for WD, approved by the FDA in 1997, showing in the process that it works by blocking copper absorption.28,29 As part of these studies, we used an absorption test for copper-64 (a simple copper salt) and showed that a minimum of 15% of ingested copper-64 bypasses the liver and adds immediately to the free copper pool of the blood.30 The copper-64 is acting as a marker of what happens to other ingested inorganic copper.
Free copper is the part of blood copper not covalently bound to ceruloplasmin (Cp). Depending on the way Cp is measured, the free copper is 5% to 35% of total blood copper. When inorganic copper is consumed, it largely bypasses the liver and enters the free copper pool of the blood directly, where it is available to cause toxicity, such as the generation of reactive oxygen species.
Squitti et al. have shown that the free blood copper is significantly elevated in AD patients compared with age-matched controls.31 This group has also shown that the level of free blood copper correlates negatively with cognition in AD (the higher the free copper, the poorer the cognition) and is a predictor of the degree of future cognition loss (the higher the free copper, the greater the rate of future cognition loss).32,33 In 2010, they measured levels of free copper in individuals already affected by mild cognitive impairment (MCI) and found that “the probability of acquiring MCI increased by about 24% for each free copper unit (µmol/L) increment.”34
Because we wanted to know how much copper our Wilson’s disease patients were ingesting, we accumulated drinking water samples from 280 households all over North America.18 We found that about a third of these samples had levels above 0.1 ppm copper, the level causing AD-type toxicity in animal models. Another third were at intermediate copper levels of unknown toxicity, and only one-third were at a level we consider completely safe, that is 0.01 ppm or less.
Thus, in countries that use copper plumbing, the copper ingested from drinking water can contribute significantly to one’s total free copper intake, a causal factor in AD. These countries are, of course, developed countries, because copper plumbing is too expensive for developing countries. As mentioned earlier, Japan is an interesting exception – a developed country with a low rate of AD. This was originally shown in a 1992 paper by Ueda et al.35 It has more recently been confirmed in a 2012 publication.36 This latter paper reviewed studies of dementia in Japan, focusing on the trends in “all cause dementia,” the sum of AD and VaD (vascular disease) dementia, which was found to be increasing in Japan, as opposed to the West. The summary statements, however, are a bit misleading with respect to the current AD frequency in Japan. If you look at the actual data in the study’s Table 3 (for those age 70–79, using the latest studies in 2005 and 2008), the all-cause dementia frequency averages about 6.7% in Japan with an AD/VaD ratio averaging about 2. Thus, the AD frequency averages about 4.5%. In the US, this age group has an AD frequency over 20%. So the low AD frequency in Japan compared with Western developed countries is confirmed in recent studies. And guess what – Japan has shunned copper plumbing, apparently for fear of copper toxicity. Yet when Japanese migrate to Hawaii, where copper plumbing is used, they develop the same high rate of AD as seen in other developed countries.37
At this point, we would like to consider the role of copper toxicity from the broad standpoint of evolution, and to include iron in this discussion, because copper and iron toxicity are very similar. They are both transition elements, which means they are redox active, transitioning between reduced and oxidized states. This property has been used in evolutionary development such that both are absolutely critical to a huge number of necessary metabolic steps, many of which require this redox effect. But this property also makes them both potentially toxic by virtue of generation of oxidant radicals as a byproduct, which, if generated in excess, can be very damaging to all sorts of molecules. Indeed, a major theory of aging is that it occurs through gradual oxidant damage.
Looking at the levels of copper and iron in the human from the standpoint of evolution, it is important to understand that evolution promotes fitness, which is measured by success in reproduction. Because copper and iron are so important to life, having adequate stores is important for reproduction. If individuals have extra stores, they are partially protected against adverse events, such as a period of famine, or trauma causing blood loss and a need for increased nutrients to repair wounds. Thus, people with increased stores are favored to reproduce; that is, they are more fit. Extra stores of these metals may cause some toxicity during reproductive years, but this does not affect fitness as long as it doesn’t hamper reproduction. The reproductive years in the human extend to about age 50, and good health in parents during the early lives of children is important in reproductive success.
After age 50, however, toxicities and diseases restricted to the aging population no longer affect reproductive success, so there is no natural selection against such diseases. This includes the toxicities associated with having too high levels of copper and iron (as long as these levels were adequately safe during the reproductive years). Thus, the levels of copper and iron that we consider normal and healthy during reproductive years are, in our view, too high after age 50 and contribute unacceptably to diseases of aging, as well as aging itself.
In the case of iron, this view is strongly supported by the hypothesis of Sullivan, now well supported by additional data that have emerged.38-40 Sullivan proposed that the reason that menstruating women have much lower risks of atherosclerosis and resulting heart disease and strokes – compared with similarly aged men – was the loss of iron in menstrual blood and the resulting lower levels of blood iron. He pointed out that at menopause, women begin catching up with men in terms of atherosclerosis. At first, critics claimed that these protective effects during the menstrual years were due to the various female hormones secreted during those years, but this has been disproved by the lack of efficacy of hormone replacement therapy after menopause.41-44
So, in this article we present the evidence for the toxicity of excess copper in the elderly, just as Sullivan has presented it for iron. And just as iron-free multivitamins are now common, copper-free supplements should be readily available, especially products used by seniors: multivitamins and eye formulas.
Can Other AD Risk Factors be Linked to Inorganic Copper Toxicity?
The answer is yes. As mentioned earlier, a high-fat diet appears to be a risk factor for AD.10 Grant has shown that the incidence of AD in various counties correlates positively with the amount of fat in the diet. The AD rabbit model used by Sparks and Schreurs was a cholesterol-fed model (although other models that were not cholesterol- or fat-fed also showed copper toxicity).22 The studies of Morris et al. that showed cognition loss in the highest quintile of copper intake also required a high-fat diet.25
To understand the synergy between inorganic copper and fat ingestion, one has to understand that copper toxicity is oxidant in nature. Because of its redox potential, involving the change of copper from one valence state (such as Cu+) to another (such as Cu++), copper can generate damaging oxidant radicals. This occurs, for example, when copper binds to amyloid plaques.3 Copper can also oxidize cholesterol and fat molecules into species that are toxic, particularly to neurons. It is part of our hypothesis that the epidemic of AD is due to not only increased ingestion of inorganic copper, but the concomitant increase in fat intake in developed countries.
Elevated homocysteine levels, a known risk factor for atherosclerosis, are also a risk factor for AD.45 Copper bound to homocysteine can oxidize cholesterol to a derivative toxic to neurons. Certain alleles of iron management genes, such as hemochromatosis or transferrin, increase the risk for AD.46,47 Iron, like copper, is a redox agent capable of generating oxidant radicals, so this fits with the overall oxidant stress hypothesis from increased copper or iron. Another risk factor appears to be zinc deficiency, discussed in the next section.48,49
We first want to point out something else. In considering the possible causal role of copper in AD, it is important to note that all the molecules involved in the brain pathology of AD are binders of copper. The amyloid precursor protein binds copper and this domain reduces Cu++ to Cu+, which produces oxidative damage.50,51 The beta secretase enzyme binds copper.3 Amyloid-beta binds copper and cholesterol, causing oxidation of cholesterol to 7-OH cholesterol.52,53 This molecule is extremely toxic to neurons. The tau protein that forms the neurofibrillary tangles, another unique feature of the AD brain, also binds copper.54 Amyloid plaques and neurofibrillary tangles in the AD brain are active producers of oxidant radicals.3 This redox activity is abolished by chelation of iron or copper, and is restored with readdition of copper or iron.3 Oxidant damage is a major feature of the AD brain. The copper binding by all these AD-related molecules does not prove that copper is playing a causal role in AD, but it helps draw the net of suspicion tighter around copper.
The Genetic Factor
Currently, the strongest evidence for an increased risk of Alzheimer’s disease is genetic, the ApoE gene. Apo is short for apolipoprotein. It has the letter E because it’s one of a whole series of apolipoproteins – A, B, C, D, and so on. The ApoE gene gets its name from the fact that it’s the part of the blueprint in charge of synthesizing apolipoprotein E, an important component of cholesterol metabolism.
In 1999, researchers first clearly demonstrated that human ApoE affects amyloid-beta metabolism, suggesting that “human ApoE particles might somehow remove amyloid out of incipient plaques the way it removes cholesterol out of atherosclerotic plaques in arteries.”55
Apolipoprotein E has three versions, or alleles: E2, E3, and E4. ApoE2 is associated with a decreased risk of developing Alzheimer’s disease. In contrast, ApoE4 markedly increases risk (and decreases age of onset). Approximately 25% of the population carries at least one copy of the ApoE4 gene, and 5% carries two copies. “If you inherit a single variant of ApoE4 from one parent, your Alzheimer’s risk triples. If you inherit a double dose of ApoE4 from both parents, your risk rises by ten times or more,” says Jean Carper in 100 Simple Things You Can Do to Prevent Alzheimer’s. (#26: Keep Copper and Iron Out of Your Brain).
The increased risk of Alzheimer’s disease for ApoE4 genotypes may relate to the inability of ApoE4 to bind copper and remove it from the brain. ApoE4 has no cysteines in a certain location in the molecule that binds copper if a cysteine is present. In contrast, ApoE2 has two cysteines that bind copper, and ApoE2 is mildly protective against the development of Alzheimer’s disease. Apo E3 is neutral regarding risk, and has one copper-binding site.
Zinc Deficiency in Alzheimer’s Disease
We know that as people age into their 60s and beyond, a large proportion become zinc deficient as measured by serum zinc. But we didn’t know if AD patients developed zinc deficiency to the same degree as other elderly. This is important, because, as we’ll review shortly, zinc has significant protective roles in the brain. So we decided to study zinc status in AD patients.
In cooperation with Earl Zimmerman’s AD group in Albany, New York, we studied 29 AD patients and 29 age-matched controls.48 Because elderly people take in a lot of nutritional supplements including zinc, and this could influence results, we stopped all supplement ingestion for one month before the study. We found that the aged controls indeed had low serum zinc levels at 83 mg/dl (young people average around 100), but AD patients were even lower at 76, a statistically significant lower value (p<0.03). A significantly lower serum zinc in AD patients compared with age-matched controls has also been seen by another group.49
There is a large amount of zinc in some neurons, and it plays very important roles. If the AD brain shares in the zinc deficiency suggested by low serum zinc, it could be part of the reason for neuronal death in AD. In certain neurons, glutamate is secreted into the synapse to initiate downstream firing, and zinc is secreted simultaneously to quench the firing.56 Excessive glutamatergic excitoactivity as a result of zinc deficiency could be very damaging to those neurons.
Another role in the brain for zinc is to inhibit calcineurin, a protein phosphatase increased in the AD brain.57 Excess calcineurin activity may adversely affect many downstream functions. Calcineurin activity is increased by exposure to amyloid-beta and inhibited by zinc, so zinc deficiency may also damage the AD brain through this mechanism.
Studies by Adlard and his group add more evidence for neuronal zinc deficiency as a cause of cognition loss. A zinc transporter called ZnT3 is the pump that loads synaptically bound vesicles in the brain with zinc. ZnT3 knockout mice, who have synaptic zinc deficiency, seem to be “a phenocopy for the synaptic and memory deficits of AD.”58 These authors found that ZnT3 levels decrease in the brains of aging humans but decrease even further in the brains of aging AD patients. They also point out that the abundant extracellular amyloid plaques in the brains of AD patients are avid zinc binders, further depleting neurons of critically important zinc.
It is possible to put together the two primary topics of this article, copper toxicity and zinc deficiency. Copper may be a major factor in amyloid plaque development and the associated copper-binding oxidant damage from these plaques. Meanwhile, the plaques bind zinc, which further depletes neurons of zinc and increases damage. If zinc deficiency is a risk factor of AD, and involved in AD progression, one could postulate that zinc therapy might have value in slowing or possibly halting AD cognition loss. In uncontrolled trials with zinc in 1992, substantial improvement in cognition was reported.59 Also a study of zinc therapy in a mouse model of AD reported improved cognitive performance in treated mice versus controls.60
Adeona Pharmaceuticals, with one of us (GJB) participating, has recently done a 6-month controlled trial of zinc therapy in AD.18 They used a new formulation that released the zinc slowly, preventing gastric irritation and prolonging elevated plasma zinc levels, allowing once-a-day administration. In the study, 60 AD patients were randomly assigned to once daily administration of 150 mg of the new zinc formulation or a matching placebo for 6 months. End points were increased levels of serum zinc, lower levels of serum free copper, and improved cognitive scoring in zinc-treated versus control subjects. Cognition was measured by ADAS-cog, MMSE, and CDR-SOB scoring tests.
The end points of significantly increased serum zinc and significantly lower serum free copper were achieved.18 All three tests showed better scores in zinc-treated patients than controls, but none were statistically significant at p = 0.05 or better, but CDR-SOB was close at p = 0.1. From the data, it was clear that placebo patients weren’t cognitively declining much until age 70, at which time they began declining rapidly, but zinc patients didn’t show that decline at age 70 or older. Statistical analysis revealed that what we had seen with our eyes was right on. Comparing the 14 zinc-treated patients with 15 placebo patients (all age 70 or over) revealed statistically significantly better scores in the zinc treated group with ADAS-cog (p = 0.037) CDR-SOB (p = 0.032), and MMSE close at p = 0.067.18 This very exciting result indicates that zinc can significantly stabilize cognition in older patients. It probably does so in younger patients as well, but it is harder to show statistically because decline in placebo patients in this group is so gradual. Because the analysis showing the significant results is considered “post hoc”; that is, generated after seeing the data rather than proposed before the study, the resulting conclusion that zinc therapy is effective at reducing or even stopping cognition loss in AD has to be considered tentative until another study is done. No one knows when that will happen, but in the meantime the results of this study, which we consider as strongly supportive, are there for all to see.
At this point, assuming that zinc benefit is correct, we don’t know whether the benefit resulted from restoring deficient zinc levels in neurons, or lowering potentially toxic high serum free copper levels, or both, because the study achieved both.
Conclusions
The first half of the article, which deals with inorganic copper from drinking water and supplement pills as a causal factor in our epidemic of AD, has to be viewed as a hypothesis. What we have as a main observation is an association between introduction of copper plumbing and increasing prevalence of copper in multivitamins with the AD epidemic. As any statistician will tell you, association does not prove causation. There are, of course, other observations that support the hypothesis. The studies which show that trace amounts of copper added to drinking water greatly enhance AD-like disease in rabbits, mice, and beagles have tested this hypothesis in animals. But animals are not humans. One can’t ethically test a potentially toxic substance by giving it to humans, but Morris et al. have come as close as one can get by studying what humans have done to themselves when ingesting a higher copper dose in vitamin supplements. It is a bit hard to visualize what study or studies would provide the definitive test that one seeks when evaluating this hypothesis. An epidemiologic study could be done, looking at whether a high proportion of those with AD, compared with age-matched controls, used copper plumbing or consumed copper supplements during their lives, but this would be very difficult.
It is not likely that a definitive test of this hypothesis will occur in the next few years, especially because there is no profit motive for a drug company to do so. In the meantime, we draw an analogy to the history of cigarette smoking. Those who took alarm three or four decades ago to the early association of cigarette smoking with lung cancer and heart attacks, and who stopped smoking, gained great benefit when it was later established that the association was causal. We liken the copper situation to the previous cigarette smoking situation. If you believe in a high likelihood that this hypothesis is correct, and therefore decrease ingestion of inorganic copper now, you will benefit greatly if it is correct.
If you wish to take action now, the following are our recommendations:
1. Discard all copper-containing nutritional supplements. Copper deficiency is rare, and most people don’t require supplementary copper, and this type of inorganic copper is dangerous. Special groups of people who may require copper supplementation are those who have had surgery that removed a part of the small intestine, those with gastric bypass surgery, those using and swallowing large quantities of dental adhesives containing zinc, and those taking a daily dose of more than 50 mg/day of zinc. All these groups should have their copper levels checked before taking a copper supplement. Everyone else should look carefully at the label of any supplements they take. Nowadays, most multivitamin formulas contain copper, as do eye formulas.
The second half of this article, which deals with zinc deficiency in AD and the likely benefit of zinc administration’s slowing or halting loss of cognition in AD, is fact based. It is a fact that, on average, AD patients are zinc deficient. It is a fact that zinc plays many roles, some of which protect against neuronal damage in the brain. It seems highly likely, but not is yet proved, that zinc therapy helps protect against cognition loss in AD. At this time, it is uncertain when a second, definitive study of zinc therapy in AD will be done.
AD patients and their families, and those who think they are at risk of developing AD, must decide for themselves whether to take zinc supplements. If they do, particularly if they take a high dose (more than 50 mg/day), it should be done under a physician’s supervision. That physician should be aware of how to monitor for copper deficiency, the main risk from high-dose zinc therapy, then lower the zinc dose if that occurs. Also, zinc must be taken between meals, because food substances bind zinc and prevent its effect on blocking copper absorption. To be clear, AD patients taking zinc should not try to compensate the partial loss of copper absorption by taking supplementary copper, because one intent of zinc therapy is to lower copper.
Measuring the free copper level in your blood: If you want to evaluate the impact of reducing your copper intake, this can theoretically be done by monitoring your free copper level, which you calculate from your serum copper and serum ceruloplasmin measured in the same blood draw.
Typically, ceruloplasmin is given as mg/dl of serum with a normal range of 20 to 35. Serum copper is given as mcg/dl of serum with a normal range of 80 to 120. Free copper in your blood is calculated by multiplying the ceruloplasmin value by 3 (because there are 3 mcg of copper per mg of ceruloplasmin), then subtracting that number from the serum copper value. For example, if your ceruloplasmin is 30, multiplied by 3 equals 90. If your serum copper is 100, 100 minus 90 equals 10 mcg/dl, the free copper level in your blood.
When ceruloplasmin is measured by the immunologic method (the one most used clinically), the normal range of free copper is 5 to 15 mcg/dl, but it may be very low or even less than 0. This is acceptable. It simply means that the free copper value is low. When ceruloplasmin is measured by the more accurate oxidase method, a normal range of free copper is about 30 to 35 mcg/dl. There is some error in these measurements, so they are a somewhat rough approximation of free copper; but as long as the same method is used consistently, you can evaluate your free copper over time.
2. What about dietary changes – are they recommended? The most effective dietary strategy to reduce both copper and iron in the body is to reduce meat intake. Both copper and iron are much more effectively absorbed (more bioavailable) from meat than from vegetable foods. One shouldn’t be confused by our suggestion here to reduce intake of meat copper, which is organic copper and which we have called “safe” copper. Our first prohibition is against ingestion of inorganic copper, because some of it contributes immediately to enlarging the serum free copper pool. But too much organic copper can also be bad, by slowly building up total body copper, which over time can gradually increase the serum free copper as well. In fact, recent studies have shown that overall health would be improved and mortality reduced if intake of meat by many in the population was lowered. A large study conducted by NIH and the American Association of Retired Persons found that people who ate about 5 ounces of red meat per day had a 30% higher mortality than those who averaged about 2/3 of an ounce. Processed meats, which include hot dogs, sausage, and bacon, also have an effect.61,62 People who ate about 60 grams (2 ounces) of processed meat per day had a 20% higher mortality than those who ate about 9 to 18 grams (about 1/3 to 2/3 ounces)/day. A similar study in Europe confirmed the effects of processed meat on mortality. The effect of higher meat eating on mortality may be due, in part, to the increased copper and iron absorption, which would increase oxidative damage, important to many disease processes besides AD, such as atherosclerosis.63
High levels of copper have been detected in US beef. Unlike other countries, the US has not established thresholds for many dangerous substances. A 2010 review by the USDA inspector general found that meat with harmful residues (dioxin, copper, arsenic, drugs, pesticides) is being distributed. In 2008, when Mexican authorities rejected a shipment of US beef because it contained copper in excess of Mexico’s tolerances, the Food Safety and Inspection Service had no basis to stop distribution of this meat in the US.64
The US government also allows unregulated residues of copper sulfate on our food. Copper sulfate (pentahydrate) is exempt from the requirement of a tolerance when applied as a bactericide/fungicide on meat, fat, and meat byproducts of cattle and hogs. Copper sulfate is also exempt from the requirement of a tolerance when applied as a fungicide to growing crops or to raw agricultural commodities after harvest.65 (Copper sulfate is the form of copper used by Sparks and Schreurs in their animal experiments.)
The top crops for copper sulfate use in California in 2009 were (in descending order): rice, wild rice, cherries, oranges, wine grapes, peaches, nectarines, walnuts, almonds, lemons, apricots, and grapefruit. Even certified organic products are allowed to contain ingredients treated with copper sulfate, which is also commonly applied to cocoa for the treatment of black pod disease. This toxic copper remains in the soil for a long time, where it’s a threat to workers as well as to water sources.
3. Test your water for copper. (Inexpensive copper test strips are available from SenSafe.com.) What copper level is safe? When rabbits consumed a concentration of 0.12 ppm (mg/L) copper in their drinking water, they had enhanced AD-type brain pathology and a decrease in cognition – their ability to carry out tasks. According to the study, these 2.2 kg rabbits consumed between 300 and 600 ml of water per day for a copper dosage of 0.016 to 0.033 mg/kg/day.22 For a 70 kg human, the equivalent dose would be 1.1 to 2.3 mg of copper per day. But extrapolations from the 10-week rabbit study are confounded by the fact that human water consumption lasts for many decades. What then is a safe concentration of copper in drinking water? We advise as close to 0 as possible, but never more than 0.05 ppm (0.05mg/L). That way, 1 liter of water would contain no more than 50 micrograms of copper.
If your water copper level is higher than that, you can filter it. A reverse osmosis system is about 99% effective at removing copper, while pitchers that use monthly disposable filters are 85% to 95% effective. Distilled water has no copper present. Bottled water is an unreliable source, because copper levels may be unknown or vary from lot to lot.
Copper corrosion in drinking water is a complex function of pipe age, water quality, stagnation time, and type of phosphate inhibitor. Disinfectant chemicals used to treat water – chlorine, ammonia, and chloramine – are all hostile to copper in that they induce copper stress cracking and/or can dissolve it. Chloramine will also react with fluosilicic acid, the most widely used water fluoridating agent, to produce ammonium fluosilicate, an established solvent for copper alloys.66
The Dartmouth Toxic Metals Superfund Research Program advises to use only water from the cold tap for drinking and for preparing food. Run the water until it gets very cold after it has been sitting in the pipes overnight. More copper leaches from hot water. Also, soft water is likely to contain more copper than hard water. Making sure that no electrical appliances are grounded to the plumbing can reduce corrosion of pipes.
Notes
1. Alzheimer’s Association. Alzheimer’s Disease Facts and Figures. 2010:1–74.
2. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. Apr 10 1992;256(5054):184–185.
3. Sayre LM, Perry G, Harris PL, Liu Y, Schubert KA, Smith MA. In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer’s disease: a central role for bound transition metals. J Neurochem. Jan 2000;74(1):270–279.
4. Alzheimer A. Ueber einer eigenartige Erkrankung der Hirnrinde. Allg. Z. Psychiatr. 1907;64:146–148.
5. Waldman M, Lamb M. Dying for a Hamburger: Modern Meat Processing and the Epidemic of Alzheimer’s Disease. 1st US ed. New York: Thomas Dune Books/St. Martin’s Press; 2005.
6. Osler W, ed. Modern Medicine in Theory and Practice. Philadelphia and New York: Lea and Febiger; 1910; No. 7.
7. Gowers WR. A Manual of Diseases of the Nervous System. Philadelphia: P. Blakiston’s Son, & Co; 1888.
8. Boyd W. A Textbook of Pathology: An Introduction to Medicine. Philadelphia: Lea and Febiger; 1938.
9. Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: A Delphi consensus study. Lancet. Dec 17 2005;366(9503):2112–2117.
10. Grant WB. Dietary links to Alzheimer’s disease. Alzheimer’s Disease Review. 1997;2:42–55.
11. Harrison P. Availability and changes in consumption of animal products. Global and regional food consumption patterns and trends. World agriculture: towards 2015/2030: summary report. Rome: Food and Agriculture Organization of the United Nations; 2002:x, 97 p.
12. Brewer GJ. The risks of free copper in the body and the development of useful anticopper drugs. Curr Opin Clin Nutr Metab Care. Nov 2008;11(6):727–732.
13. Brewer GJ. The risks of copper toxicity contributing to cognitive decline in the aging population and to Alzheimer’s disease. J Am Coll Nutr. Jun 2009;28(3):238–242.
14. Brewer GJ. Risks of copper and iron toxicity during aging in humans. Chem Res Toxicol. Feb 15 2010;23(2):319–326.
15. Brewer GJ. Copper toxicity in the general population. Clin Neurophysiol. Apr 2010;121(4):459–460.
16. Brewer GJ. Toxicity of copper in drinking water. J Toxicol Environ Health B Crit. Rev. Aug 2010;13(6):449–452.
17. Brewer GJ. Issues raised involving the copper hypotheses in the causation of Alzheimer’s disease. Int J Alzheimers Dis. 2011;2011:537528.
18. Brewer GJ. Copper excess, zinc deficiency, and cognition loss in Alzheimer’s disease. Biofactors. Mar–Apr 2012;38(2):107–113.
19. Brewer GJ. Copper toxicity in Alzheimer’s disease: cognitive loss from ingestion of inorganic copper. J Trace Elem Med Biol. Jun 2012;26(2–3):89–92.
20. Brewer GJ. Metals in the causation and treatment of Wilson’s disease and Alzheimer’s disease, and copper lowering therapy in medicine. Inorganica Chimica Acta. 2012;393(0):135–141.
21. Eskici G, Axelsen PH. Copper and oxidative stress in the pathogenesis of Alzheimer’s disease. Biochemistry. Aug 14 2012;51(32):6289–6311.
22. Sparks DL, Schreurs BG. Trace amounts of copper in water induce beta-amyloid plaques and learning deficits in a rabbit model of Alzheimer’s disease. Proc Natl Acad Sci U S A. Sep 16 2003;100(19):11065–11069.
23. Sparks DL, Friedland R, Petanceska S, et al. Trace copper levels in the drinking water, but not zinc or aluminum, influence CNS Alzheimer-like pathology. J Nutr Health Aging. 2006;10(4):247–254.
24. Deane R, Zlokovic B, et al. A novel role for copper: Disruption of LRP-dependent brain Abeta clearance. Paper presented at: Annual Meeting of the Society for Neuroscience; Nov 3–7, 2007; San Diego, CA; see also Singh I, Sagare AP, Coma M, et al. Low levels of copper disrupt brain amyloid-ß homeostasis by altering its production and clearance. PNAS. August 19, 2013; doi:10.1073/pnas.1302212110.
25. Morris MC, Evans DA, Tangney CC, et al. Dietary copper and high saturated and trans fat intakes associated with cognitive decline. Arch Neurol. Aug 2006;63(8):1085–1088.
26. Gahche J, Bailey R, Burt V, et al. Dietary supplement use among U. S. adults has increased since NHANES III (1988–1994). NCHS Data Brief. Apr 2011(61):1–8.
27. Brewer GJ. Wilson’s Disease. In: Longo D, Fauci A, Kasper D, Hauser S, Jameson J, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18 ed. New York: McGraw-Hill Companies; 2011.
28. Yuzbasiyan-Gurkan V, Grider A, Nostrant T, Cousins RJ, Brewer GJ. Treatment of Wilson’s disease with zinc: X. Intestinal metallothionein induction. J Lab Clin Med. Sep 1992;120(3):380–386.
29. Brewer GJ, Dick RD, Johnson VD, Brunberg JA, Kluin KJ, Fink JK. Treatment of Wilson’s disease with zinc: XV long-term follow-up studies. J Lab Clin Med. Oct 1998;132(4):264–278.
30. Hill GM, Brewer GJ, Juni JE, Prasad AS, Dick RD. Treatment of Wilson’s disease with zinc. II. Validation of oral 64copper with copper balance. Am J Med Sci. Dec 1986;292(6):344–349.
31. Squitti R, Pasqualetti P, Dal Forno G, et al. Excess of serum copper not related to ceruloplasmin in Alzheimer disease. Neurology. Mar 22 2005;64(6):1040–1046.
32. Squitti R, Barbati G, Rossi L, et al. Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF [beta]-amyloid, and h-tau. Neurology. Jul 11 2006;67(1):76–82.
33. Squitti R, Bressi F, Pasqualetti P, et al. Longitudinal prognostic value of serum “free” copper in patients with Alzheimer disease. Neurology. Jan 6 2009;72(1):50–55.
34. Squitti R, Ghidoni R, Scrascia F, et al. Free copper distinguishes mild cognitive impairment subjects from healthy elderly individuals. J Alzheimers Dis. 2011;23(2):239–248.
35. Ueda K, Kawano H, Hasuo Y, Fujishima M. Prevalence and etiology of dementia in a Japanese community. Stroke. Jun 1992;23(6):798–803.
36. Dodge HH, Buracchio TJ, Fisher GG, et al. Trends in the prevalence of dementia in Japan. Int J Alzheimers Dis. 2012;2012:956354.
37. White L, Petrovitch H, Ross GW, et al. Prevalence of dementia in older Japanese-American men in Hawaii: The Honolulu-Asia Aging Study. JAMA. Sep 25 1996;276(12):955–960.
38. Sullivan JL. Iron and the sex difference in heart disease risk. Lancet. Jun 13 1981;1(8233):1293–1294.
39. Sullivan JL. Are menstruating women protected from heart disease because of, or in spite of, estrogen? Relevance to the iron hypothesis. Am Heart J. Feb 2003;145(2):190–194.
40. Sullivan JL. Is stored iron safe? J Lab Clin Med. Dec 2004;144(6):280–284.
41. Gordon T, Kannel WB, Hjortland MC, McNamara PM. Menopause and coronary heart disease. The Framingham Study. Ann Intern Med. Aug 1978;89(2):157–161.
42. Kannel WB, Hjortland MC, McNamara PM, Gordon T. Menopause and risk of cardiovascular disease: the Framingham study. Ann Intern Med. Oct 1976;85(4):447–452.
43. Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med. Aug 24 2000;343(8):522–529.
44. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. Aug 19 1998;280(7):605–613.
45. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. Feb 14 2002;346(7):476–483.
46. Moalem S, Percy ME, Andrews DF, et al. Are hereditary hemochromatosis mutations involved in Alzheimer disease? Am J Med Genet. Jul 3 2000;93(1):58–66.
47. Zambenedetti P, De Bellis G, Biunno I, Musicco M, Zatta P. Transferrin C2 variant does confer a risk for Alzheimer’s disease in caucasians. J Alzheimers Dis. Dec 2003;5(6):423–427.
48. Brewer GJ, Newsome DA. Toxic Copper: The Newly Discovered Culprit in Alzheimer’s Disease and Dementia. Ann Arbor, MI: Raisin Publishing LLC; 2010.
49. Baum L, Chan IH, Cheung SK, et al. Serum zinc is decreased in Alzheimer’s disease and serum arsenic correlates positively with cognitive ability. Biometals. Feb 2010;23(1):173–179.
50. Multhaup G, Schlicksupp A, Hesse L, et al. The amyloid precursor protein of Alzheimer’s disease in the reduction of copper(II) to copper(I). Science. Mar 8 1996;271(5254):1406–1409.
51. White AR, Multhaup G, Galatis D, et al. Contrasting, species-dependent modulation of copper-mediated neurotoxicity by the Alzheimer’s disease amyloid precursor protein. J Neurosci. Jan 15 2002;22(2):365–376.
52. Huang X, Atwood CS, Hartshorn MA, et al. The A beta peptide of Alzheimer’s disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry. Jun 15 1999;38(24):7609–7616.
53. Nelson TJ, Alkon DL. Oxidation of cholesterol by amyloid precursor protein and beta-amyloid peptide. J Biol Chem. Feb 25 2005;280(8):7377–7387.
54. Ma Q, Li Y, Du J, et al. Copper binding properties of a tau peptide associated with Alzheimer’s disease studied by CD, NMR, and MALDI-TOF MS. Peptides. Apr 2006;27(4):841–849.
55. Holtzman DM, et al. Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer’s disease. J Clin Invest. 1999 Mar;103(6):R15–R21.
56. Takeda A. Insight into glutamate excitotoxicity from synaptic zinc homeostasis. Int J Alzheimers Dis. 2010;2011:491597.
57. Crouch PJ, Savva MS, Hung LW, et al. The Alzheimer’s therapeutic PBT2 promotes amyloid-beta degradation and GSK3 phosphorylation via a metal chaperone activity. J Neurochem. Oct 2011;119(1):220–230.
58. Adlard PA, Parncutt JM, Finkelstein DI, Bush AI. Cognitive loss in zinc transporter-3 knock-out mice: a phenocopy for the synaptic and memory deficits of Alzheimer’s disease? J Neurosci. Feb 3 2010;30(5):1631–1636.
59. Constantinidis J. Treatment of Alzheimer’s disease by zinc compounds. Drug Dev Res. 1992;27(1):1–14.
60. Corona C, Masciopinto F, Silvestri E, et al. Dietary zinc supplementation of 3xTg-AD mice increases BDNF levels and prevents cognitive deficits as well as mitochondrial dysfunction. Cell Death Dis. 2010;1:e91.
61. Sinha R, Cross AJ, Graubard BI, Leitzmann MF, Schatzkin A. Meat intake and mortality: a prospective study of over half a million people. Arch Intern Med. Mar 23 2009;169(6):562–571.
62. Liebman B. The real cost of red meat. Nutrition Action Health Letter. 2009;June.
63. Rohrmann S, Overvad K, Bueno-de-Mesquita HB, et al. Meat consumption and mortality – results from the European Prospective Investigation into Cancer and Nutrition. BMC Med. 2013;11:63.
64. FSIS National Residue Program for Cattle. Washington DC: US Department of Agriculture, Office of Inspector General; 2010.
65. Copper sulfate pentahydrate; tolerance exemption in or on various food and feed commodities. Vol. 71: Fed Reg. 2006.
66. Maas RP, Patch SC, Christian AM, Coplan MJ. Effects of fluoridation and disinfection agent combinations on lead leaching from leaded-brass parts. Neurotoxicology. Sep 2007;28(5):1023–1031.
Dr. George J. Brewer is Sellner Professor Emeritus of Human Genetics and Emeritus Professor of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
John D. MacArthur is a neuroscience writer whose report, “Overdosed: Fluoride, Copper, and Alzheimer’s Disease,” is published in this issue of the Townsend Letter.
