A few decades ago, some small, preliminary studies hinted that aluminum might be linked to Alzheimer’s disease. Headlines immediately screamed about this newly discovered danger, people threw away aluminum cookware, and everyone from deodorant manufacturers to food producers began advertising “aluminum free” formulations to assuage public fears.
It was all a big misunderstanding. The original findings turned out to be an artifact, and subsequent analyses either found that aluminum was completely unrelated to Alzheimer’s disease, or that it might even have a mild protective effect, if any. Search for “aluminum Alzheimer’s” on the internet today, and the top hits are mostly debunking this old error. Unfortunately, the corrections have never quite caught up to the original myth. “Aluminum free” persists as an advertising claim, and the old chestnut about it causing Alzheimer’s disease still crops up regularly.
Now here we go again, but with a twist. Yesterday, a paper in the Proceedings of the National Academy of Sciences explored the role of copper in the metabolism of amyloid beta protein. Amyloid beta is the protein that aggregates to form plaques in the brains of Alzheimer’s disease patients. News coverage of this new work followed a sadly predictable pattern. This BBC story is among the most balanced pieces on it, but even they went with a highly misleading headline.
Unfortunately, this isn’t just a repeat of the aluminum debacle. In that case, some very sparse results yielded a very simple hypothesis, which some very obvious checking destroyed. With the new copper story, we have a thorough and interesting piece of work adding to a large body of existing data, all feeding into a highly complex model of disease pathogenesis. Even before this study came out, if someone had wanted to drum up fear about copper, it would have been easy to pull up an entire shelf of peer-reviewed literature about this metal’s connection to Alzheimer’s disease.
But things are not as they appear. If you delved into that shelf of literature, you’d quickly discover a story that defies brief summaries and sound bites. It’s a reporter’s nightmare.
To understand the depth of the problem, take a look at the new paper. It’s free for anyone to download (the PDF is here). If you think it’s tough to read, you’re not alone. I have a Ph.D. in a related field and have spent years immersed in scientific writing, and I find the Alzheimer’s literature pretty gnarly. Just looking at the introduction, you can see that this isn’t the first time people have connected copper with Alzheimer’s disease; the first few paragraphs cite a lot of the literature I just alluded to.
Copper is an essential nutrient. You can’t live without it, as it’s required for several metabolic processes. On the other hand, high doses of copper are toxic. As usual, the dose makes the poison. Amyloid beta protein is also a normal part of our metabolism, and so is Tau, another protein implicated in Alzheimer’s disease. The relative importance of amyloid beta and Tau is the subject of longstanding debate in the Alzheimer’s research community, but it’s clear that both proteins seem to malfunction when the disease develops. Copper metabolism also goes awry. Notice I haven’t said anything about which event causes which. All we can say is that all of these things, and more, correlate with the progression of Alzheimer’s disease.
Besides dose, the effect of copper seems to depend on context. If you add low levels of copper to the drinking water of rabbits or beagles, they develop accumulations of amyloid beta in certain parts of their brains. That’s not to say they develop Alzheimer’s disease, just that the copper seems to change the normal amyloid metabolism somehow. However, if you take transgenic mice overexpressing the amyloid-beta precursor protein and give them extra copper, it reduces amyloid beta levels in the animals’ brains. So copper may cause amyloid beta to accumulate, or to dissipate, depending on how you ask the question.
In the new paper, the authors treated mice with 0.13 mg/L of copper in their drinking water. That’s 1/10 the EPA limit for ordinary drinking water. In genetically normal lab mice, the copper accumulates in the small blood vessels in the brain, but not in the nervous tissue. This pattern of copper accumulation seems to reduce the levels of a protein called LRP1, which normally helps transport amyloid beta out of the brain for disposal. In a transgenic mouse model of Alzheimer’s disease, copper accumulates in both the blood vessels and the nervous tissue. With this pattern of copper accumulation, the scientists saw a reduction in LRP1 and also an increase in amyloid beta production and inflammation in the nervous tissue. Copper’s pleiotropic effects seem to depend on where it piles up and what else is going on around it.
The researchers also did some interesting biochemical experiments to look at the mechanisms behind copper accumulation in the brain, and they’ve developed a pretty good model that might eventually yield some promising drug leads. What they most certainly haven’t done, don’t purport to do, and should never, ever be cited as having done, is show that copper causes Alzheimer’s disease. So let’s not imply that, okay?