The genetics of Alzheimer’s disease is complicated and still somewhat mysterious. But in the last week, researchers reported on two new genetic approaches that may have long-range potential for preventing this calamitous brain destroyer.
One set of results, published in papers in Nature Neuroscience, seemed at first to pile an additional layer of complexity on an already complex disorder. Two research groups have zeroed in on epigenetic factors associated with the disease. Yet the findings may eventually turn out to simplify therapies and even preventive measures.
Some of their discoveries agree, increasing the likelihood that both groups have identified epigenetic mechanisms that really are important in development of Alzheimer’s. On the other hand, the associations are just that–associations. If these epigenetic events do play a role in the disease, at this point it’s not clear whether they are involved in causing Alzheimer’s or are a consequence of it.
Epigenetic mechanisms, you’ll recall, are molecular structures that change a gene’s behavior without changing its DNA sequence. Think of epigenetics as a collection of ways that environmental influences shape gene activity.
The epigenetics of unhealthy lifestyles
Writing in New Scientist, the journalist Andy Coghlan noted there’s already evidence that an unhealthy lifestyle and inflammatory diseases like diabetes increase the risk of Alzheimer’s. “The new research hints that the lifestyle changes that raise Alzheimer’s risk may be taking effect through epigenetic changes,” he said.
The research groups, based in the US and UK, found the epigenetic factors by studying brain tissue from about 1200 people, some who had Alzheimer’s and some who did not. (Brain tissue can only be extracted and studied after death.)
The research focused on the most common and most investigated epigenetic mechanism: methylation, the process of attaching reversible chemical tags called methyl groups to DNA. (A methyl group is a small molecule made of one carbon atom bonded to three hydrogen atoms, CH3.) Methylation usually turns genes on.
Both groups identified the same gene as being hypermethylated in some brain regions where the pathological changes are most evident in Alzheimer’s disease. The gene, which does not seem to have been previously associated with Alzheimer’s, is called ANK1. It appears to have a role in cell membranes.
The paper from the British research group, led by Jonathan Mill of the University of Exeter Medical School, observed that hypermethylation of ANK1 “represents one of the most robust molecular associations with AD [Alzheimer’s disease] yet identified.” The other study, led by Philip De Jager of Brigham and Women’s Hospital in Boston, identified hypermethylated ANK1 but also hypermethylation of six other genes connected to a known Alzheimer susceptibility gene network.
Confirmation that hypermethylation is involved in the development of Alzheimer’s disease could have an enormous impact because epigenetic changes are often reversible. It might mean that drugs, or perhaps even dietary changes, can prevent this awful disease. One potential caution: Coghlan points out that some epigenetic effects were detected in brain tissue from people who had displayed no Alzheimer’s symptoms. That might mean that the changes have more to do with normal brain aging than with pathology.
Is a nonworking APOE gene a Good Thing?
You may well have heard of the second gene that made news for Alzheimer’s disease. It’s by far the best known: APOE, which regulates blood lipids. APOE comes in different versions. One of them, APOE4, has long been known to raise the risk of Alzheimer’s disease substantially. This variant codes for a defective protein and is fairly common, occurring in about 20% of the population.
Just last spring research revealed that the increased risk of APOE4 affected women far more than men. (You can read about this research, and other genes involved in Alzheimer’s disease, in a column I did here at GLP in April.)
The research, published a week ago in an open-access paper in JAMA Neurology, reported on a man whose APOE genes were mutated in a way that disabled them completely. He has some weird medical conditions, mainly involving fatty deposits accumulating under his skin, some of them large and painful and all of them disfiguring. But the researchers, based at the University of California-San Francisco, found that he seems to have normal brain function despite his nonworking APOE.
His normal brain function suggests that APOE might not be so important for the brain after all. It also suggests that a strategy of disabling APOE4, the most dangerous form of the gene, might greatly reduce Alzheimer’s disease risk without damage to the brain.
Pam Belluck writes in the New York Times that APOE‘s job in the brain appears to be clearing out the protein beta-amyloid. This protein is thought to be responsible for the buildup of brain plaques that lead to Alzheimer’s disease. APOE4 is slow to clear out the protein clogs, but another gene variant, APOE2, disposes of them quickly. And the absence of a working APOE gene, the new paper reports, appears to dispose of them even more quickly.
This might mean that an anti-APOE therapy would not have serious neurological side effects. Such a therapy would be tricky to devise, though, because it would have to work in the brain without affecting lipid handling in the liver. Mouse studies have been encouraging, Belluck reports.
The paper suggests that either the protein APOE codes for is not critical for brain function, or else whatever it’s doing that is critical can be done by some other protein. Surprisingly enough, the researchers say, it appears that having an APOE gene that doesn’t work at all may be better for the brain than having the risky APOE4 variant coding for its defective protein.
Tabitha M. Powledge is a long-time science journalist and a contributing columnist for the Genetic Literacy Project. She also writes On Science Blogs for the PLOS Blogs Network. Follow her @tamfecit.