G J Brewer

University of Michigan, Ann Arbor, Michigan, United States

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Publications (268)1143.32 Total impact

  • Journal of Trace Elements in Medicine and Biology 09/2014; · 1.96 Impact Factor
  • George J Brewer, Ananda S Prasad
    Journal of the American College of Nutrition 05/2014; 33(3):185. · 1.74 Impact Factor
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    George J Brewer
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    ABSTRACT: Evidence will be presented that the Alzheimer's disease (AD) epidemic is new, the disease being very rare in the 1900s. The incidence is increasing rapidly, but only in developed countries. We postulate that the new emerging environmental factor partially causal of the AD epidemic is ingestion of inorganic copper from drinking water and taking supplement pills, along with a high fat diet. Inorganic copper can be partially directly absorbed and elevate the serum free copper pool. The Squitti group has shown that serum free copper is elevated in AD, correlates with cognition, and predicts cognition loss. Thus, our inorganic copper hypothesis fits well with the Squitti group data. We have also shown that AD patients are zinc deficient compared to age-matched controls. Because zinc is a neuronal protective factor, we postulate that zinc deficiency may also be partially causative of AD. We carried out a small 6 month double blind study of a new zinc formulation and found that in patients age 70 and over, it protected against cognition loss. Zinc therapy also significantly reduced serum free copper in AD patients, so efficacy may come from restoring normal zinc levels, or from lowering serum free copper, or from both.
    Frontiers in Aging Neuroscience 01/2014; 6:92. · 5.20 Impact Factor
  • George J Brewer
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    ABSTRACT: Tetrathiomolybdate (TM) is a unique anticopper drug developed for the treatment of the neurologic presentation of Wilson's disease, for which it is excellent. Since it was known copper was required for angiogenesis, TM was tested on mouse cancer models to see if it would inhibit tumor growth based on an antiangiogenic effect. TM was extremely effective in these models, but all the tumors in the models started small in size – micromestastic in size. Later, TM was tested in numerous human cancer trials, where it showed only modest effects. However, the mouse lesson of efficacy against micro disease was forgotten – all the trials were against bulky, advanced cancer. Now, the mouse evidence is coming back to life. Three groups are curing, or having major efficacy of TM, against advanced human cancers, heretofore virtually incurable, particularly if the cancer has been reduced to no evidence of disease (NED) status by conventional therapy. In that situation, where the remaining disease is micrometastic, TM therapy appears to be curative. We have designed and initiated a study of TM in canine osteosarcoma at the micrometastic phase to help put these findings on a firm scientific basis. TM also has major anti-inflammatory properties by inhibiting copper dependent cytokines involved in inflammation. This anti-inflammatory effect may be involved in TM's anticancer effect because cancers, as they advance, attract inflammatory cells that provide a plethora of additional proangiogenic agents.
    Journal of Trace Elements in Medicine and Biology 01/2014; · 1.96 Impact Factor
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    George J Brewer, Sukhvir Kaur
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    ABSTRACT: We are in the midst of an epidemic of Alzheimer's disease (AD) in developed countries. We have postulated that ingestion of inorganic copper from drinking water and taking supplement pills and a high fat diet are major causative factors. Ingestion of inorganic copper can directly raise the blood free copper level. Blood free copper has been shown by the Squitti group to be elevated in AD, to correlate with cognition, and to predict cognition loss. Secondly, we have shown that AD patients are zinc deficient compared to age matched controls. Zinc is important in neuronal protection. We carried out a 6-month small double blind trial of a new zinc formulation on AD patients. We found that in patients 70 years and older, zinc therapy protected against cognition decline compared to placebo controls. We also found that zinc therapy significantly lowered blood free copper levels. So zinc efficacy could be due to restoring neuronal zinc levels, to lowering blood free copper levels, or to both.
    International journal of Alzheimer's disease. 01/2013; 2013:586365.
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    International journal of Alzheimer's disease. 01/2013; 2013:838274.
  • George J Brewer
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    ABSTRACT: In this review I present the hypothesis that a toxic substance, inorganic copper, ingested from drinking water and vitamin/mineral supplements containing inorganic copper, is at least partially causal of the epidemic of Alzheimer's disease (AD) we are seeing in developed countries. I set the stage for this hypothesis by pointing out that the epidemic is a new disease phenomenon coinciding temporally with the use of copper plumbing in developed countries. The evidence is good that AD was nonexistent or rare in the 1800 s and early 1900 s, and the arguments that elderly people did not exist in those times, or that AD was simply attributed to senility, are refuted. The web of evidence tying ingestion of inorganic copper as a causal factor in AD is strong, and includes AD animal model data where trace amounts of inorganic copper in the drinking water markedly worsened AD, human studies where ingestion of copper supplements, along with a high fat diet, is associated with a marked loss of cognition, human studies showing a markedly higher mortality in elderly women ingesting copper supplements, as well as other data. It is likely that a high fat diet works in conjunction with ingestion of inorganic copper to increase the risk of AD. It is clear that some factor toxic to the brain is present in the environment in developed countries, but not undeveloped countries, and is a major risk factor for AD. I believe that that toxic factor is ingestion of inorganic copper.
    Journal of Trace Elements in Medicine and Biology 06/2012; 26(2-3):89-92. · 1.96 Impact Factor
  • George J. Brewer
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    ABSTRACT: Appropriate anticopper therapy for Wilson’s disease is the critical element in halting progression of the disease and allowing patient recovery. Selection of the drug or drugs to use for a particular patient depends on the stage of the disease (ie, initial acutely ill patient versus chronic maintenance patient) and the type of presentation (ie, neurologic/psychiatric versus hepatic). I treat patients initially presenting with hepatic disease with a combination of zinc and trientine, those presenting with neurologic/psychiatric disease with tetrathiomolybdate, and those in the maintenance phase with zinc.
    Current Treatment Options in Neurology 04/2012; 2(3):193-203. · 1.94 Impact Factor
  • George J Brewer
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    ABSTRACT: In this special issue about biofactors causing cognitive impairment, we present evidence for and discuss two such biofactors. One is excess copper, causing neuronal toxicity. The other is zinc deficiency, causing neuronal damage. We present evidence that Alzheimer's disease (AD) has become an epidemic in developed, but not undeveloped, countries and that the epidemic is a new disease phenomenon, beginning in the early 1900s and exploding in the last 50 years. This leads to the conclusion that something in the developed environment is a major risk factor for AD. We hypothesize that the factor is inorganic copper, leached from the copper plumbing, the use of which coincides with the AD epidemic. We present a web of evidence supporting this hypothesis. Regarding zinc, we have shown that patients with AD are zinc deficient when compared with age-matched controls. Zinc has critical functions in the brain, and lack of zinc can cause neuronal death. A nonblinded study about 20 years ago showed considerable improvement in AD with zinc therapy, and a mouse AD model study also showed significant cognitive benefit from zinc supplementation. In a small blinded study we carried out, post hoc analysis revealed that 6 months of zinc therapy resulted in significant benefit relative to placebo controls in two cognitive measuring systems. These two factors may be linked in that zinc therapy significantly reduced free copper levels. Thus, zinc may act by lowering copper toxicity or by direct benefit on neuronal health, or both.
    BioFactors 03/2012; 38(2):107-13. · 3.09 Impact Factor
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    ABSTRACT: Wilson disease patients present with any of several neurologic phenotypes, and their treated outcomes vary widely. Our goal was to determine whether presenting clinical features of neurologic Wilson disease (WD) predict longer term neurologic outcomes in patients receiving anticopper treatment. Patients enrolled in four WD treatment trials received a standardized neurologic examination at trial enrollment and then at pre-specified intervals following anticopper therapy, initially with tetrathiomolybdate or trientine and then with zinc. The examination scored patients' motor signs, including tremor, rigidity, dystonia, dyarthria, and gait. The Total Score was obtained by summing these subscores. Eighty-six patients were included in our analysis, with a mean follow-up of 34.7 months. Retrospectively, the analysis compared scaled and unscaled sign subscores at enrollment and follow-up with change in the Total Score, using a generalized estimating equations approach. In the primary analysis, improvement in the Total Score was best predicted by sign subscores for tremor (beta -0.7, p = 0.006), gait abnormalities (beta -3.7, p < 0.001), and speech (beta = -1.3, p = 0.05). Dystonia (beta = 1.8, p < 0.001) and facial expression (beta = 1.9, p = 0.03) were associated with worsening Total Score. Of the motor signs followed individually, dystonia proved most resistant to treatment. This is the first large-scale prospectively acquired study assessing prognostic significance of specific neurologic signs in WD. Our data support the historical observations that tremor is a favorable prognostic sign while dystonia is relatively refractory to treatment in WD.
    Parkinsonism & Related Disorders 06/2011; 17(7):551-6. · 3.27 Impact Factor
  • Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2011; 7(4).
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    George J Brewer
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    ABSTRACT: I present evidence that the epidemic of Alzheimer's disease is a new phenomenon exploding in the latter part of the 20th century in developed countries. I postulate that a major causative factor in the epidemic is the coincident use of copper plumbing, and the ingestion of inorganic copper leaching from the copper plumbing. I present evidence to support this hypothesis and discuss various objections and criticisms that have been raised about the hypothesis, and my responses to these criticisms. I conclude that the hypothesis is well supported by the evidence and deserves serious consideration, because if it is valid, it indentifies a partially preventable cause of Alzheimer's disease.
    International journal of Alzheimer's disease. 01/2011; 2011:537528.
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    International journal of Alzheimer's disease. 01/2011; 2011:903940.
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    ABSTRACT: To evaluate zinc status in Alzheimer's disease and Parkinson's disease, 29 patients with Alzheimer's disease, 30 patients with Parkinson's disease, and 29 age- and sex-matched controls were studied. All patients and controls were older than age 50, and all zinc and copper supplements were prohibited beginning 30 days prior to study. Patients were diagnosed by standard criteria. Blood zinc and urine zinc were measured. Urine zinc was measured in a casual specimen, standardized for dilution by reference to creatinine content. Results showed a significantly lower blood zinc in patients with Alzheimer's and patients with Parkinson's than in controls. Urine zinc excretion, normalized to urine creatinine excretion, was not significantly different in either patient group compared to controls. These patients are probably zinc deficient because of nutritional inadequacy.
    American Journal of Alzheimer s Disease and Other Dementias 11/2010; 25(7):572-5. · 1.52 Impact Factor
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    ABSTRACT: The idea that copper may play a role in the pathogenesis of Alzheimer's disease is gaining momentum. Serum copper and ceruloplasmin were measured by both enzymatic (eCp) and immunologic (iCp) methods in 28 patients with Alzheimer's disease and 29 age-matched controls. ''Free copper'' was determined by subtracting copper accounted for in the eCp assay from total serum copper. Percentage free copper, that is the proportion of serum copper not bound to ceruloplasmin, was significantly elevated in patients with Alzheimer's compared to controls. There was significantly more ''defective'' ceruloplasmin, which is apoceruloplamin lacking its copper, in Alzheimer's disease than in normal controls. This abnormality may precede the clinical onset of the disease and help predict risk of disease onset. Increased exposure to environmental copper (eg, the spread of copper plumbing and the use of copper in supplements) and/or defective ceruloplasmin function may play a role in the current epidemic of Alzheimer's disease.
    American Journal of Alzheimer s Disease and Other Dementias 09/2010; 25(6):490-7. · 1.52 Impact Factor
  • George J Brewer
    Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 04/2010; 121(4):459-60. · 3.12 Impact Factor
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    ABSTRACT: The results of a double-blind trial of tetrathiomolybdate therapy and standard of care, versus placebo and standard of care treatment, in primary biliary cirrhosis patients are presented. Baseline studies of liver function, various safety variables, ceruloplasmin, a liver biopsy for histologic analysis, and for various cytokine analyses were carried out. Patients were observed every 4 months for up to 2 years of treatment by a hepatologist for clinical evaluation and repeat of all the baseline studies except liver biopsy, which was repeated at 2 years. The primary end points were improvement in 2 liver function tests and in 1 inflammatory cytokine. Fifteen placebo patients were followed for an average of 13 months, and 13 tetrathiomolybdate patients were followed for an average of 14 months. The predefined primary end points for efficacy were met. Tetrathiomolybdate was well tolerated. Because tetrathiomolybdate has been shown in numerous animal studies to inhibit autoimmune and inflammatory processes, and because primary biliary cirrhosis is an autoimmune attack on bile ducts, these positive findings on efficacy of tetrathiomolybdate therapy in primary biliary cirrhosis fit with the animal studies and suggest the need for a longer clinical trial to examine transplant-free survival.
    Translational research : the journal of laboratory and clinical medicine. 03/2010; 155(3):123-30.
  • Journal of Toxicology and Environmental Health Part B 01/2010; 13(6):449-459. · 3.90 Impact Factor
  • George J Brewer
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    ABSTRACT: Orphan diseases are diseases that are found in less than 200,000 patients in the United States, which is the cutoff point for the number of patients for a drug to be profitable. Because many thousands of orphan diseases exist in the aggregate (about 20 to 30 million Americans have orphan diseases), these patients are disenfranchised from drug development by the pharmaceutical industry. Orphan drugs are a large part of personalized medicine. The orphan diseases are often so rare that a physician may observe only 1 case a year or less. So proper treatment is a personalized encounter between doctor and patient. Academic physician-scientists have tried to fill this therapy vacuum by working on developing orphan drugs. But many disincentives are involved, which include career disincentives, lack of funding, and the multiple areas of expertise that are required. Positive developments include formation of the National Organization for Rare Diseases, the Orphan Drug Act, the development of a grant program to fund orphan drug development, the formation of the National Institutes of Health Office of Rare Diseases, and the passage of orphan drug legislation by other countries. Progress has increased, but the 300 orphan drugs and devices approved in the last 25 years are still only a drop in the bucket compared with the many thousands of orphan diseases. I believe we must do better. I present my own 2 examples of the positive and the negative aspects of orphan drug development, and I end this article by giving recommendations on how we might succeed both in developing more orphan drugs and in rescuing the pharmaceutical industry from its impending economic collapse.
    Translational research : the journal of laboratory and clinical medicine. 12/2009; 154(6):314-22.
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    George J Brewer
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    ABSTRACT: 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.
    Chemical Research in Toxicology 12/2009; 23(2):319-26. · 3.67 Impact Factor

Publication Stats

6k Citations
1,143.32 Total Impact Points

Institutions

  • 1967–2014
    • University of Michigan
      • • Department of Human Genetics
      • • Department of Internal Medicine
      • • Department of Neurology
      Ann Arbor, Michigan, United States
    • Loyola University
      New Orleans, Louisiana, United States
  • 1964–2013
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2009
    • Vanderbilt University
      • Department of Neurology
      Nashville, MI, United States
  • 2008
    • National Institutes of Health
      Maryland, United States
  • 1993–1999
    • Michigan State University
      • • College of Veterinary Medicine
      • • Department of Small Animal Clinical Sciences
      East Lansing, MI, United States
  • 1998
    • Beth Israel Deaconess Medical Center
      Boston, Massachusetts, United States
  • 1973–1997
    • Wayne State University
      • • Department of Internal Medicine
      • • School of Medicine
      Detroit, MI, United States
  • 1978
    • University of Milan
      Milano, Lombardy, Italy