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. 1. Introduction We are in the midst of an epidemic of Alzheimer’s disease (AD), particularly in developed countries [1]. We have previously hypothesized that ingestion of inorganic copper from drinking water and supplement pills and a high fat diet are main causal factors in AD [2–5]. These two factors interact synergistically because copper oxidizes fats to molecules that are toxic, particularly to neurons. The epidemic correlates temporally with the use of copper plumbing in developed countries, and there is a great amount of additional data that draws the net tighter around a causative role for inorganic copper. Inorganic copper must not be confused with organic copper, the copper in food that is safely bound to protein. Inorganic copper is a simple salt of copper, not bound to anything, and is in part handled differently by the intestinal absorption mechanism, such that some of it contributes immediately to the serum free copper pool [6]. This pool has been shown by Squitti and her group to be expanded in AD [7], to correlate negatively with cognition [8], and to predict deterioration in cognition [9]. So, our inorganic copper hypothesis fits well with the work of the Squitti et al. group. While we believe ingestion of inorganic copper and a high fat diet are major causal factors, there are a number of other known risk factors in AD. These include having an apolipoprotein E4 allele [10], having elevated homocysteine levels [11], or having certain alleles of the iron management genes, hemochromatosis [12] and transferrin [13]. These latter fit with the copper hypothesis
References
[1]
Alzheimer's Association, “Alzheimer's disease facts and figures,” 2010.
[2]
G. J. Brewer, “The risks of copper toxicity contributing to cognitive decline in the aging population and to Alzheimer's disease,” Journal of the American College of Nutrition, vol. 28, no. 3, pp. 238–242, 2009.
[3]
G. J. Brewer, “Issues raised involving the copper hypotheses in the causation of Alzheimer's disease,” International Journal of Alzheimer's Disease, vol. 2011, Article ID 537528, 11 pages, 2011.
[4]
G. J. Brewer, “Copper toxicity in Alzheimer's disease: cognitive loss from ingestion of inorganic copper,” Journal of Trace Elements in Medicine and Biology, vol. 26, no. 2-3, pp. 89–92, 2012.
[5]
G. J. Brewer, “Metals in the causation and treatment of Wilson’s disease and Alzheimer’s disease, and copper lowering therapy in medicine,” Inorganica Chimica Acta, vol. 393, pp. 135–141, 2012.
[6]
G. M. Hill, G. J. Brewer, and J. E. Juni, “Treatment of Wilson's disease with zinc. II. Validation of oral 64 coppper with copper balance,” American Journal of the Medical Sciences, vol. 292, no. 6, pp. 344–349, 1986.
[7]
R. Squitti, P. Pasqualetti, G. Dal Forno et al., “Excess of serum copper not related to ceruloplasmin in Alzheimer disease,” Neurology, vol. 64, no. 6, pp. 1040–1046, 2005.
[8]
R. Squitti, G. Barbati, L. Rossi et al., “Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF β-amyloid, and h-tau,” Neurology, vol. 67, no. 1, pp. 76–82, 2006.
[9]
R. Squitti, F. Bressi, P. Pasqualetti et al., “Longitudinal prognostic value of serum “free” copper in patients with Alzheimer disease,” Neurology, vol. 72, no. 1, pp. 50–55, 2009.
[10]
M. Miyata and J. D. Smith, “Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and β-amyloid peptides,” Nature Genetics, vol. 14, no. 1, pp. 55–61, 1996.
[11]
S. Seshadri, A. Beiser, J. Selhub et al., “Plasma homocysteine as a risk factor for dementia and Alzheimer's disease,” The New England Journal of Medicine, vol. 346, no. 7, pp. 476–483, 2002.
[12]
S. Moalem, M. E. Percy, D. F. Andrews, et al., “Are hereditary hemochromatosis mutations involved in Alzheimer disease?” American Journal of Medical Genetics, vol. 93, no. 1, pp. 58–66, 2000.
[13]
P. Zambenedetti, G. De Bellis, I. Biunno, M. Musicco, and P. Zatta, “Transferrin C2 variant does confer a risk for Alzheimer's disease in caucasians,” Journal of Alzheimer's Disease, vol. 5, no. 6, pp. 423–427, 2003.
[14]
S. Bucossi, S. Mariani, M. Ventriglia et al., “Association between the c. 2495 A>G ATP7B polymorphism and sporadic Alzheimer's disease,” International Journal of Alzheimer's Disease, vol. 2011, Article ID 973692, 9 pages, 2011.
[15]
G. J. Brewer, S. H. Kanzer, E. A. Zimmerman et al., “Subclinical zinc deficiency in Alzheimer's disease and Parkinson's disease,” American Journal of Alzheimer's Disease and other Dementias, vol. 25, no. 7, pp. 572–575, 2010.
[16]
L. Baum, I. H. S. Chan, S. K.-K. Cheung et al., “Serum zinc is decreased in Alzheimer's disease and serum arsenic correlates positively with cognitive ability,” Biometals, vol. 23, no. 1, pp. 173–179, 2010.
[17]
A. Takeda, “Insight into glutamate excitotoxicity from synaptic zinc homeostasis,” International Journal of Alzheimer's Disease, vol. 2011, Article ID 491597, 8 pages, 2011.
[18]
P. J. Crouch, M. S. Savva, L. W. Hung et al., “The Alzheimer's therapeutic PBT2 promotes amyloid-β degradation and GSK3 phosphorylation via a metal chaperone activity,” Journal of Neurochemistry, vol. 119, no. 1, pp. 220–230, 2011.
[19]
P. A. Adlard, J. M. Parncutt, D. I. Finkelstein, and A. I. Bush, “Cognitive loss in zinc transporter-3 knock-out mice: a phenocopy for the synaptic and memory deficits of Alzheimer's disease?” Journal of Neuroscience, vol. 30, no. 5, pp. 1631–1636, 2010.
[20]
J. Constantinidis, “Treatment of Alzheimer's disease by zinc compounds,” Drug Development Research, vol. 27, no. 1, pp. 1–14, 1992.
[21]
C. Corona, F. Masciopinto, E. Silvestri et al., “Dietary zinc supplementation of 3xTg-AD mice increases BDNF levels and prevents cognitive deficits as well as mitochondrial dysfunction,” Cell Death & Disease, vol. 1, article e91, 2010.
[22]
G. J. Brewer, R. D. Dick, V. D. Johnson, J. A. Brunberg, K. J. Kluin, and J. K. Fink, “Treatment of Wilson's disease with zinc: XV long-term follow-up studies,” Journal of Laboratory and Clinical Medicine, vol. 132, no. 4, pp. 264–278, 1998.
[23]
P. L. Wolf, “Ceruloplasmin: methods and clinical use,” Critical Reviews in Clinical Laboratory Sciences, vol. 17, no. 3, pp. 229–245, 1982.
