ARTICLE IN BRIEF
✓ Scientists say the association between copper and Alzheimer disease is based on no fewer than five animal models, a large epidemiologic study, numerous in vitro studies and, now, a compelling model for how it might function in the brain.
More than a decade after a handful of studies frightened consumers into tossing out their aluminum pots and pans for fear of a link to Alzheimer disease (AD), a new study has put the spotlight on copper.
But while they're both metals, scientists studying the association say the case for copper is far stronger than aluminum's ever was, based on no fewer than five animal models, a large epidemiologic study, numerous in vitro studies and, now, a compelling model for how it might function in the brain.
Still, researchers are eager to avoid a repeat of the aluminum scare, saying that not all the data has been consistent and that human trials are necessary before clinical recommendations should be made to patients.
“I think the jury is still out,” said Ashley I. Bush, MD, PhD, of the Genetics and Aging Unit at Harvard Medical School. “There's a growing literature about copper exposure increasing the risk for Alzheimer pathology, but we need more studies to determine whether the risk is robust for humans.”
Copper's Effect on the Brain
The latest study, described at the Society for Neuroscience meeting in San Diego on Nov. 6, attempted to discern a mechanism behind prior observations that copper is found at high levels within amyloid plaques, and that trace levels of copper in drinking water reduces the clearance of amyloid-beta from the brain of normal rabbits.
Researchers at the University of Rochester reported that the main receptor for clearing amyloid-beta from the brain, a molecule known as LRP (low-density lipoprotein receptor-related protein) stopped functioning in the presence of copper.
“We found out what copper does to the transporter,” said Rashid Deane, PhD, associate professor of neurological surgery. “It actually degrades the LRP in the endothelial cells lining the brain. This degradation means there is less transport of amyloid from the brain.”
The laboratory study, which used cells from the brains of people who had died of AD, was complemented by a study in mice, half of whom were fed water with .12 mg of copper per liter (less than one-tenth the Environmental Protection Agency's limit for drinking water) and half fed distilled water without copper.
Mice fed copper had about twice as much of the metal in their endothelial cells as the control mice, about one-third fewer LRP molecules and one-third more amyloid beta in their brains after 10 weeks.
The author of an epidemiologic study published in the August 2006 Archives of Neurology showing a strong link between copper intake and cognitive decline said the new study may explain why she and others have found the link only in those eating a diet high in saturated and trans fats.
“From my perspective, it was really interesting that the mechanism was linked to the LDL receptor molecule,” said Martha Clare Morris, SciD, associate professor of internal medicine at the Rush Institute for Healthy Aging and assistant provost for community research at Rush University Medical Center. “In my data, I didn't see that copper is bad for you unless you have a diet that would lead to hypercholesterolemia. So the fact that the LDL receptor is involved in this is fascinating to me.”
Dr. Morris's community-based prospective study of 3,718 participants aged 65 and older included four cognitive tests administered during in-home interviews at three-year intervals for six years, with dietary assessment performed with a food frequency questionnaire.
Among those who ate a high-fat diet, the difference in rates of cognitive decline for people in the highest quintiles of total copper intake was –6.14 standardized units per year (p<.001) or the equivalent of 19 or more years of age. A strong dose-response association was observed with higher copper dose in vitamin supplements.
“There are now five different animal models that have demonstrated the same dietary intake of copper related to amyloid-beta pathology and to poorer cognitive functioning in these animal models,” Dr. Morris said. “It's been seen in dogs, rats, mice, rabbits. Then there are some phase 1 and 2 clinical trials under way, and the epidemiologic study. That's some pretty strong evidence. That's very different than the aluminum story.”
Dr. Bush, who has been a leader in the study of metals and neurologic functioning, said that the undue media coverage given to a handful of aluminum studies in the early 1990s has made it difficult for researchers studying the effects of other metals on neurologic functioning.
“Scientists not familiar with this subject tend to lump all metals together,” said Dr. Bush in an interview from his office in Victoria, Australia, where, in addition to his position at Harvard, he is professor in the Oxidation Biology Laboratory at the Mental Health Research Institute of Victoria. “That's like saying all proteins are the same. I certainly have had to battle to inform critics about the basic science involved. It's made funding difficult and publications difficult. But the percentage of papers involving metals in AD now represents about 2 percent of all AD papers — that's quadrupled in the last 10 years.”
Dr. Bush and colleagues have just completed a phase 2 trial of a drug, called PBT2, that in animal models rescues copper trapped in extracellular amyloid and returns it to relatively depleted intracellular stores, resulting in rapidly improved cognitive functioning in mice. The data on the 80-person trial will be unblinded in January, said Dr. Bush, who has a financial stake in the company that owns the drug, Prana Biotechnology.
Interest in copper began heating up when D. Larry Sparks, PhD, a senior scientist at the Sun Health Institute in Sun City, Arizona, reported in the September 2003 issue of the Proceedings of the National Academy of the Sciences that cholesterol-fed rabbits developed signs of AD only when also given trace amounts of copper in their water. Dr. Sparks, whose research on the use of atorvastatin to prevent AD had already come to the attention of neurologists, made the copper observation by chance.
“About the time we stated conducting the first human trial of atorvastatin in humans to prevent Alzheimer disease, the rabbit model that it was all built on stopped working,” Dr. Sparks said. “None of the rabbits were developing AD, whether or not we gave them atorvastatin. After 16 months of changing everything but the personnel in the lab, I went down to the vivarium, and saw they were lined with these blue bottles. I said, ‘What's that?’ ‘That's the spring water we give to the animals.’ I said, ‘Now I want to do the studies all over, and have half the animals get the bottled waters, and half get tap water.’ Only the animals fed tap water developed Alzheimer disease. It was the copper in the tap water.”
One puzzling aspect of the copper story is that some researchers have found a metabolic deficiency of the metal associated with AD. For example, a 2005 paper in the Journal of Alzheimer's Disease found cognitive decline correlated with low plasma copper levels in patients with mild to moderate AD.
A possible solution to the puzzle was suggested by a July 2006 study in Neurology that reported that only the small portion of copper not bound to ceruloplasmin in the blood raises the risk of AD. “It's largely this unbound small fraction of copper that people need to measure,” Dr. Deane said. “But some people are measuring different fractions of the total copper. That leads to confusion in the field.”
Dr. Bush's view, laid out in a lengthy review article in the November 2006 Journal of Alzheimer's Disease, is that the problem is essentially a maldistribution of copper. “It looks like the copper is pooling outside the cell, being trapped by the beta amyloid, and can't get back into the cell,” he said. “That's the best way to reconcile all these findings.”
In the meanwhile, neurologists can stay tuned for neurologic outcomes among the four researchers whose work has been quoted here: all four have given up drinking unfiltered tap water, which typically contains trace levels of copper.