Alzheimer's and Inflammation

Two online letters, just out in Nature Genetics (here and here), found three genes that had a statistically significant correlation with late-onset Alzheimer's disease. For the past 16 years, only one gene, APOE, had been connected with this common form of the disease, explaining about half of its genetic heritability. In contrast, the rare, early-onset form has a more classic "Mendelian" genetic pattern, in which, if you have a mutation in one of three genes, you have a high probability of getting the disease.

The new results have the common disappointments of the last few years of genome-wide association studies, or GWAS, of complex diseases: (1) The effects of any particular genetic variant are weak, so they can only be seen by studying thousands of subjects. (2) Because half a million candidate mutations are tested simultaneously, it's hard to assess the significance of something that looks like an association. It's easy to pick up false positives by chance alone, so researchers need to apply big corrections. (3) Different studies identify different variants. In this case, the studies agree on a gene called CLU, but each of them also finds another gene that the other study doesn't. (4) The cumulative effect of all the variants found is not enough to explain the observed heritability of the disease. It seems that there must be many other, unidentified contributors, each having only a small effect.

Confirming this weakness, co-author Michael Owen, of Cardiff University in Wales, noted in a supplementary statement on the Nature Genetics website that "the current genes on their own are not strong predictors of risk and are not suitable for risk testing." I'll have a lot more to say about GWAS and disease in future posts.

But although the genes aren't very useful for predicting risk, they do give clues about the biological mechanisms of the disease. Most previous discussions of Alzheimer's, including these two papers, concerns two types of protein deposits in brain cells: "plaques" of β-amyloid protein and "tangles" of tau protein. Both of these deposits are often seen in the brains of Alzheimer's patients after they die. Clusterin, which is the protein coded by CLU, may help clean up the plaques.

But in her supplementary statement, Julie Williams, also of Cardiff, noted that "clusterin has a role in dampening down inflammation in the brain. Up until now increased inflammation seen in the brains of Alzheimer's sufferers had been viewed as a secondary effect of disease. Our results suggest the possibility that inflammation may be primary to disease development."

This reminded me of Paul Ewald's talk at a January 2007 symposium at Hunter College, "Evolution, Health, and Disease," which I covered on behalf of the New York Academy of Sciences. Ewald, of the University of Louisville, noted that inflammation of arterial plaques is a common feature of the atherosclerosis that often leads to heart disease. (The test for inflammation using the C-reactive protein (CRP) is often used to predict heart-attack risk.) But he also noted that the troublesome ε4 variant of the EPOE gene "is the major risk factor, not only for atherosclerosis and stroke, but also for sporadic Alzheimer's and multiple sclerosis," even though the fat transport that influences atherosclerosis is a completely different chemical property than the formation of protein plaques in Alzheimer's or the myelin-sheath destruction in multiple sclerosis. "The idea that ε4 would be bad in all of these different ways," Ewald said, "is really stretching it."

Instead, Ewald suspects that the common element in these various diseases is infection, perhaps by Chlamydia pneumonia. I imagine that his view remains on the fringe, and perhaps it will remain there. But 25 years ago, the idea that many ulcers are caused by a bacteria was also a fringe idea. Barry Marshall and Robin Warren won the 2005 Nobel Prize in Physiology or Medicine for tracing ulcers to Helicobacter pylori. Maybe in 25 years we will find it natural to associate Alzheimer's with infection, too.