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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.
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