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From the Townsend Letter
October 2013

Too Much Copper, Too Little Zinc, and Cognitive Deterioration in Alzheimer's Disease
by George J. Brewer, MD, and John D. MacArthur
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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.

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