Some new work from our group has just gone online over at Metallomics. Pinning down the role of zinc in Alzheimer’s disease has long been a challenge to people in the AD field. In 1994, our colleague Ashley Bush found that zinc induces the formation of beta-amyloid aggregates, which are a common feature of the disease, made up predominately of a short peptide that is thought to be the major cause of toxicity in AD. Since then, zinc has been the focus of much AD research, but directly associating an element that has a number of important brain functions with a drawn-out disease process is no mean feat.
The Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing, or AIBL for short, is a project run by the CSIRO and a number of academic partners in Melbourne and Perth that consists of one of the world’s largest assembled group of AD patients, complete with healthy controls and a number of people classified as being ‘mildly cognitively impaired’, several of who have transitioned to AD over the 54+ months the study has been active for. Among other things, AIBL is designed to help find a viable biomarker to AD so that diagnosis might be possible long before disease symptoms occur. One of the many targets for the AIBL study is zinc in serum, considering the numerous studies that have previously reported a decrease in zinc in people with AD, and it’s apparent role in beta-amyloid plaque formation. Using the 1,000+ serum samples in AIBL, we found something else interesting about zinc…
After analysing every single serum sample taken at the start of the AIBL project, we initially found that, indeed, there was a statistically significant decrease in our AD group. At first, this seemed to fit well with what we thought we knew about zinc in AD, but on closer observation it turns out things were a little more complex. Several key variables needed to be assessed to make sure our observations held to rigorous statistical testing. Firstly, there are certain genetic factors that have an effect on your susceptibility to develop AD, the most prominent of which is known as your ApoE genotype. Individuals who carry the e4 allele can be up to 30 times more likely to develop the disease (though, non-e4’s also can develop AD, and not all e4s will either). Examining these groups, independent of disease classification, turned out no different between the zinc levels of each genotype. Check one.
Next was sex. The AIBL study has thought of this previously, and the number of males to females is pretty much equal. However, an older paper from 1989 has previous suggested a sex-based difference in serum zinc levels. With the added statistical power of the AIBL study, we were able to identify that this observed difference was likely a statistical anomaly.
Finally, we needed to examine the effect of age, the one major factor in which AIBL isn’t equal. As makes logical sense, people with AD tend to be older than healthy controls in studies of this size. AIBL is no different, with an average age difference between the two groups of just over 8 years. As it would turn out, this tends to be something we see in a lot of other studies looking at AD and control groups, and in the case of zinc this happens to be quite important. When we compared each case against the others, completely independent of disease classification, a very slight, but very significant trend began to emerge. Sure enough, the older a subject was, the less zinc we found in their serum:
Once we take this factor into account, our previously observed trend of decreased serum zinc in AD vanished. A consequence of our AD cohort being older is that, on average, their serum zinc levels are lower. In fact, we were able to estimate that the rate of decrease in zinc levels in serum went down by 0.4% per year. Take the 8 year age gap into account and that 0.4% per year accounts for our observed difference between AD and controls.
What’s the importance of this study, considering we didn’t find a change in AD patients’ serum zinc levels? This is the first study of its kind with sufficient numbers to categorically state that serum zinc is not decreased in AD. By the nature of the samples themselves, many studies looking into this idea previously have been hampered by small data sets, which may present trends that aren’t actually real when we increase the number of samples analysed. This by no means suggests that zinc isn’t somehow involved in AD, after all, serum certainly isn’t the brain, but it hopefully will provide useful information to others trying to chase down the elusive role of zinc in this disease.