Copper-2 Hypothesis for Causation of the Current Alzheimer's Disease Epidemic Together with Dietary Changes That Enhance the Epidemic.

Alzheimer's disease, the most common cause of dementia, is at epidemic proportions (15 to 44% depending on age, of those age 65 to 84) in the U.S. and other developed countries but remains relatively rare in undeveloped countries. Surprisingly, solid historical data reveal the epidemic is a creature of the last century. That is, the disease was also rare in developed countries, until the 20th century. It is disappointing that these historical and demographic facts have been ignored by the Alzheimer's disease scientific community. Disappointing because these facts clearly point at an environmental change in the 20th century in developed countries as a major factor in causing the epidemic. Some scientists have discarded the claimed rarity of the disease in the 19th century as incorrect, saying that Alzheimer's disease is a disease of aging and that the increasing lifespan of people accounts for the current high prevalence of the disease, but this cavalier attitude ignores historical data indicating there were many elderly people in the 19th century who were not getting Alzheimer's disease with any significant frequency. In this review, after documenting that the observed assertions about historical and demographic facts are correct, evidence is amassed that the main environmental culprit causing the Alzheimer's epidemic is ingestion of divalent copper or copper-2. The two sources of copper-2 ingestion are drinking water and multimineral supplement pills containing copper. The increase in copper plumbing use in developed countries parallels the increasing prevalence of Alzheimer's disease. It has been shown that enough copper is leached from copper plumbing in most households to cause Alzheimer's disease, using the Alzheimer's disease animal model studies as a guide to toxic levels. It is relatively easy to avoid or greatly diminish copper-2 ingestion by not using copper containing supplement pills and testing drinking water for copper levels. If the copper in water is too high, a simple device can be put on the tap to remove copper. In addition to the copper-2 hypothesis, this review covers dietary changes that enhance the epidemic.

Risks of copper and iron toxicity during aging in humans.

Copper and iron are essential but also toxic metals. Their essentiality is known, but their toxicity, except for the genetic overload diseases, Wilson's disease and hemochromatosis, is not so well known. Yet, their toxicities are so general in the population that they are a looming public health problem in diseases of aging and in the aging process itself. Both metals are transition elements, and their resulting redox properties have been used during evolution in the development of oxidative energy generation. But both contribute to the production of excess damaging oxidant radicals. Evolution has kept stores of copper and iron in excess during the reproductive years because they are so vital to life. But the oxidant damage from these excess stores of metals builds up as we age, and natural selection ceases to act after about age 50 since diseases after that do not contribute to reproductive fitness. Diseases of aging such as Alzheimer's disease, other neurodegenerative diseases, arteriosclerosis, diabetes mellitus, and others may all be contributed to by excess copper and iron. A very disturbing study has found that in the general population those in the highest fifth of copper intake, if they are also eating a relatively high fat diet, lose cognition at over three times the normal rate. Inorganic copper in drinking water and in supplements is handled differently than food copper and is therefore more toxic. Trace amounts of copper in drinking water, less than one-tenth of that allowed in human drinking water by the Environmental Protection Agency, greatly enhanced an Alzheimer's-like disease in an animal model. In the last part of this review, I will provide advice on how to lower risks from copper and iron toxicity.

A pilot trial of the anti-angiogenic copper lowering agent tetrathiomolybdate in combination with irinotecan, 5-flurouracil, and leucovorin for metastatic colorectal cancer.

Tetrathiomolybdate (TM) is an oral copper chelator under development as an anti-angiogenic agent. We evaluated TM in combination with irinotecan, 5-fluorouracil, and leucovorin (IFL). Serum vascular endothelial growth factor (VEGF), basic fibroblast growth factor, interleukin 6 (IL-6), and IL-8 were measured to evaluate the anti-angiogenic effect. Twenty-four patients with metastatic colorectal cancer were treated. The combination with IFL was well tolerated and dose intensity of IFL was maintained during combination therapy with TM. By intention to treat analysis, the overall response rate (RR) was 25% (95% CI 9.8-46.7) and the median time to progression (TTP) was 5.6 months (95% CI 2.7-7.7). VEGF levels were correlated with TTP, as were changes in VEGF, IL-8, and IL-6. TM can be safely added to IFL without compromising dose intensity or diminishing the expected RR. Changes in serum VEGF, IL-8, and IL-6 after treatment may directly reflect changes in CRC tissue angiogenesis.

The risks of copper toxicity contributing to cognitive decline in the aging population and to Alzheimer's disease.

It is a pleasure and an honor to contribute a paper to a special issue of the Journal of the American College of Nutrition honoring Stanley Wallach and Pearl Small. In this brief review I advance the hypothesis that copper toxicity is the major cause of the epidemic of mild cognitive impairment and Alzheimer's disease engulfing our aging population. This epidemic is recent, exploding in the last 50-60 years. The disease was virtually unknown 100 years ago. And it involves only developed countries that use copper plumbing. Something in our environment associated with development is poisoning the minds of our aged. The epidemic is associated with the use of copper plumbing, and the taking of copper in multi-mineral supplements. Food copper (organic copper) is processed by the liver and is transported and sequestered in a safe manner. Inorganic copper, such as that in drinking water and copper supplements, largely bypasses the liver and enters the free copper pool of the blood directly. This copper is potentially toxic because it may penetrate the blood/brain barrier. I review a web of animal and human data that tightens the noose around the hypothesis that copper toxicity is causing the epidemic of Alzeimer's disease and loss of cognition in our aging population.

Evaluation of tetrathiomolybdate in the R6/2 model of Huntington disease.

Huntington disease is an uncommon autosomal dominant neurodegenerative disorder caused by expanded polyglutamine repeats in the huntingtin protein. The proximate mechanisms responsible for neurodegeneration are unknown. Copper ions may play a role in Huntington disease by promoting oligomerization of expanded polyglutamine repeat protein fragments. Ammonium tetrathiomolybdate is a copper complexing agent with demonstrated tolerability and efficacy in another neurodegenerative disorder, Wilson disease. We evaluated ammonium tetrathiomolybdate in the R6/2 transgenic mouse model of Huntington disease. Ammonium tetrathiomolybdate treatment delayed the onset of motor dysfunction in R6/2 mice. There was a trend towards reduced striatal degeneration, suggesting a neuroprotective effect of ammonium tetrathiomolybdate in this model. Given its known tolerability in humans with neurodegeneration, ammonium tetrathiomolybdate could be considered as a candidate for clinical trials in Huntington disease.

Improvement in dissolution of liver fibrosis in an animal model by tetrathiomolybdate.

The background for this study is that we have observed some improvement in cirrhosis in Wilson's disease patients treated with the anticopper medicine, zinc, and another anticopper drug, tetrathiomolybdate, has completely prevented hepatic fibrosis in the carbon tetrachloride mouse model. We hypothesize that in existing cirrhosis, there may be a fine balance between fibrosis formation and fibrosis dissolution, which may be pushed in the direction of dissolution by anticopper drugs. Thus, in this study, we produced hepatic fibrosis in mice by treatment with carbon tetrachloride, then gave half the fibrotic mice tetrathiomolybdate for 3 months, while the other half of the fibrotic mice received nothing for 3 months and served as controls. Tetrathiomolybdate caused a dramatic and significant reduction in fibrosis as measured by hydroxyproline (the major amino acid constituent of collagen) levels, almost back to baseline levels, compared to controls, who had only a slight and nonsignificant reduction. It is clear from this animal study that dissolution of preexisting fibrosis can be strongly catalyzed by lowering copper levels with tetrathiomolybdate. It now becomes important to evaluate whether this approach will work in the human epidemic of cirrhotic disease resulting from diseases such as alcoholism, nonalcoholic steatohepatitis, and hepatitis C.

Avoiding Alzheimer's disease: The important causative role of divalent copper ingestion.

IMPACT STATEMENT: The work described in this review is very important to scientists working on Alzheimer's disease (AD) because it reveals a cause for the explosive epidemic of this disease. It is also important to the public because it provides a method to avoid this newly revealed cause, and thereby avoid AD. The field is advanced because this review reveals new information about the mechanism of AD pathogenesis, namely copper, and specifically divalent copper, toxicity is important. New information about divalent copper toxicity in the brain affecting cognition is revealed. The field is impacted strongly because, in view of the frustrations that have occurred in treatment developed, now most AD can be prevented. This means the suffering of the patient, the prolonged and difficult care required by caregivers, and the enormous expenditures for this one disease, can now be avoided.

Tetrathiomolybdate protects against bile duct ligation-induced cholestatic liver injury and fibrosis.

Tetrathiomolybdate (TM), a potent copper-chelating drug, was initially developed for the treatment of Wilson's disease. Our working hypothesis is that the fibrotic pathway is copper-dependent. Because biliary excretion is the major pathway for copper elimination, a bile duct ligation (BDL) mouse model was used to test the potential protective effects of TM. TM was given in a daily dose of 0.9 mg/mouse by means of intragastric gavage 5 days before BDL. All the animals were killed 5 days after surgery. Plasma liver enzymes and total bilirubin were markedly decreased in TM-treated BDL mice. TM also inhibited the increase in plasma levels of tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1 seen in BDL mice. Cholestatic liver injury was markedly attenuated by TM treatment as shown by histology. Hepatic collagen deposition was significantly decreased, and it was paralleled by a significant suppression of hepatic smooth muscle alpha-actin and fibrogenic gene expression in TM-treated BDL mice. Although the endogenous antioxidant ability was enhanced, oxidative stress as shown by malondialdehyde and 4-hydroxyalkenals, hepatic glutathione/oxidized glutathione ratio, was not attenuated by TM treatment, suggesting the protective mechanism of TM may be independent of oxidative stress. In summary, TM attenuated BDL-induced cholestatic liver injury and fibrosis in mice, in part by inhibiting TNF-alpha and TGF-beta1 secretion. The protective mechanism seems to be independent of oxidative stress. Our data provide further evidence that TM might be a potential therapy for hepatic fibrosis.

Tetrathiomolybdate is partially protective against hyperglycemia in rodent models of diabetes.

The objective was to evaluate whether copper lowering therapy with tetrathiomolybdate (TM) affected blood sugar levels in three rodent models of diabetes, streptozotocin (STZ) treated rats and mice, and the db/db mouse model. STZ was administered to rats and mice, and blood sugar levels were followed over a protracted time in these and non-STZ control animals. TM was administered by oral gavage (rats) or in the drinking water (mice) to a portion of the rats and mice to observe effects on blood sugar. Mice with genetically determined diabetes (db/db) were studied by giving half the mice TM in the drinking water and following blood sugar. The results show that TM caused a significant reduction in blood glucose in both STZ treated rats and mice, but no effect on blood glucose in db/db mice. However, TM caused a significant reduction in proteinuria in db/db animals. The results are discussed around the likelihood that TM is inhibiting ongoing inflammatory damage in the pancreas from STZ. A metabolic effect of TM on blood glucose is possible but seems less likely. TM is also likely inhibiting inflammatory and/or fibrogenic effects in the kidneys of db/db mice.

Iron and copper toxicity in diseases of aging, particularly atherosclerosis and Alzheimer's disease.

In this review, we point out that natural selection does not act to lessen human diseases after the reproductive and caregiving period and that normal levels of iron and copper that may be healthy during the reproductive years appear to be contributing to diseases of aging and possibly the aging process itself. It is clear that oxidant damage contributes to many of the diseases of aging, such as atherosclerosis, Alzheimer's disease, Parkinson's diseases, diabetes, diseases of inflammation, diseases of fibrosis, diseases of autoimmunity, and so on. It is equally clear that both iron and copper can contribute to excess production of damaging reactive oxygen species through Fenton chemistry. Here, we examine the evidence that "normal" levels of iron and copper contribute to various diseases of aging.

Treatment of Wilson disease with ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease.

OBJECTIVE: To compare tetrathiomolybdate and trientine in treating patients with the neurologic presentation of Wilson disease for the frequency of neurologic worsening, adverse effects, and degree of neurologic recovery. DESIGN: A randomized, double-blind, controlled, 2-arm study of 48 patients with the neurologic presentation of Wilson disease. Patients either received 500 mg of trientine hydrochloride 2 times per day or 20 mg of tetrathiomolybdate 3 times per day with meals and 20 mg 3 times per day between meals for 8 weeks. All patients received 50 mg of zinc 2 times per day. Patients were hospitalized for 8 weeks, with neurologic and speech function assessed weekly; discharged taking 50 mg of zinc 3 times per day, and returned annually for follow-up. SETTING: A university hospital referral setting. PATIENTS: Primarily newly diagnosed patients with Wilson disease presenting with neurologic symptoms who had not been treated longer than 4 weeks with an anticopper drug. INTERVENTION: Treatment with either trientine plus zinc or tetrathiomolybdate plus zinc. MAIN OUTCOME MEASURES: Neurologic function was assessed by semiquantitative neurologic and speech examinations. Drug adverse events were evaluated by blood cell counts and biochemical measures. RESULTS: Six of 23 patients in the trientine arm and 1 of 25 patients in the tetrathiomolybdate arm underwent neurologic deterioration (P<.05). Three patients receiving tetrathiomolybdate had adverse effects of anemia and/or leukopenia, and 4 had further transaminase elevations. One patient receiving trientine had an adverse effect of anemia. Four patients receiving trientine died during follow-up, 3 having shown initial neurologic deterioration. Neurologic and speech recovery during a 3-year follow-up period were quite good. CONCLUSION: Tetrathiomolybdate is a better choice than trientine for preserving neurologic function in patients who present with neurologic disease.

The use of tetrathiomolybdate in treating fibrotic, inflammatory, and autoimmune diseases, including the non-obese diabetic mouse model.

Tetrathiomolybdate was originally developed for use in Wilson's disease. However, lowering copper levels to below normal levels with tetrathiomolybdate has been found to have efficacy in cancer, probably by turning down signaling by angiogenic cytokines. More recently, we have shown in animals models that tetrathiomolybdate dramatically inhibits pulmonary and liver fibrosis. In other animal models, we have shown that the drug also inhibits liver damage from concanavalin A and acetaminophen, and heart damage from doxorubicin. These studies are briefly reviewed, and we then present data on tetrathiomolybdate's partially protective effect against diabetes in non-obese diabetic mice, an autoimmune model of type I diabetes. Possible mechanisms of tetrathiomolybdate's protective effect are briefly considered.

Copper lowering therapy with tetrathiomolybdate as an antiangiogenic strategy in cancer.

Tetrathiomolybdate (TM) is a novel anticopper agent under development for use in Wilson's disease. It acts by forming a stable tripartite complex with serum albumin and copper, rendering the complexed copper unavailable for cellular uptake. TM is a very potent anticopper agent and has an excellent safety profile. It has been shown that normal copper levels are required for optimal angiogenesis. Based on this background, we decided to evaluate TM as an anticancer agent. TM treatment of Her/2neu mice, genetically programmed to develop breast cancer, completely prevented the development of visible mammary cancers, although avascular microscopic clusters of cancer cells were present in the breasts of TM treated animals. Controls developed grossly visible tumors. TM was able to strongly inhibit tumor growth in six other rodent models. In a phase 1/2 clinical trial of advanced and metastatic cancers, freedom from progression averaged 11 months, and some individual results were quite dramatic. Eight phase 2 studies of specific cancers have been launched. TM's hypothesized mechanism of action is inhibition of angiogenic cytokines. Unlike other current approaches to antiangiogenic therapy which target single agents, we hypothesize that TM inhibits multiple angiogenic cytokines. Part of this effect appears to stem from inhibition of nuclear factor kappa B (NF(K)B), which in turn controls transcription of many angiogenic and other cytokines. However, there are probably multiple mechanisms, in that some angiogenic cytokines appear to have separate mechanisms of copper dependence. The inhibition of multiple angiogenic cytokines gives TM the potential to be a more global inhibitor of angiogenesis.

Control of copper status for cancer therapy.

Copper is a trace element which is tightly regulated in mammals and lower animals. Disruptions of copper homeostasis in humans are rare and they cause serious disorders such as Wilson's disease and Menke's disease. Copper plays an important role in promoting physiological and malignant angiogenesis. Formation of new blood vessels by a tumor enables tumor growth, invasion, and metastasis are copper requiring processes. The copper chelator tetrathiomolybdate (TM), which quickly and effectively depletes copper stores, is under investigation as an anti-angiogenic agent. Promising results from in vitro experiments, in pre-clinical animal models, and in a phase I clinical trial have led to several phase II trials of TM in patients with advanced cancers.

Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesis.

Copper plays an essential role in promoting angiogenesis. Tumors that become angiogenic acquire the ability to enter a phase of rapid growth and exhibit increased metastatic potential, the major cause of morbidity in cancer patients. We report that copper deficiency induced by tetrathiomolybdate (TM) significantly impairs tumor growth and angiogenesis in two animal models of breast cancer: an inflammatory breast cancer xenograft in nude mice and Her2/neu cancer-prone transgenic mice. In vitro, TM decreases the production of five proangiogenic mediators: (a) vascular endothelial growth factor; (b) fibroblast growth factor 2/basic fibroblast growth factor; (c) interleukin (IL)-1alpha; (d) IL-6; and (e) IL-8. In addition, TM inhibits vessel network formation and suppresses nuclear factor (NF)kappaB levels and transcriptional activity. Our study suggests that a major mechanism of the antiangiogenic effect of copper deficiency induced by TM is suppression of NFkappaB, contributing to a global inhibition of NFkappaB-mediated transcription of proangiogenic factors.

Reply to B. Meunier's Letter to the Editor Re: Brewer G. J.; Nutrients 2015, 7, 10053-10064.

In a letter to the editor, Meunier [1] apparently attempts to discredit the copper-2 hypothesis for causation of the Alzheimer's disease (AD) epidemic in developed countries proposed by myself in a review in this journal [2].[...].

Correction: Brewer, G.J. Copper-2 Ingestion, Plus Increased Meat Eating Leading to Increased Copper Absorption, Are Major Factors Behind the Current Epidemic of Alzheimer's Disease. Nutrients 2015, 7(12), 10053-10064.

On page 10055, line 10, of the original publication [1] it was incorrectly stated that "However, this argument is invalid because in 1911, half the population of France was 60 or older".[...].