Several proteins are linked to an increased risk of Alzheimer’s disease, and scientists now believe they have found the pathways responsible for producing these compounds.
For decades, Alzheimer’s researchers have known that changes in amyloid and tau proteins in the brain and spinal fluid signal the beginning stages of the neurodegenerative disorder. As amyloid levels build up in the brain, forming sticky plaques that can destroy nerve cells, levels of tau, a protein formed from the debris of dying or dead neurons, also increase, eventually hampering critical cognitive functions such as memory and executive functions.
But what triggers these changes? In a study published in the journal Neuron, researchers focusing on tau say they have successfully traced some of these changes to a group of receptors that appear on the surface of cells; one group increased the risk for the disease by boosting tau production while the other seemed to protect against tau formation.
In order to hone in on the genetic variants associated with tau, the researchers performed a genome wide association study (GWAS) involving 687 healthy elderly participants and 591 elderly patients diagnosed with clinical Alzheimer’s disease. All agreed to spinal taps so the scientists could measure the levels of amyloid-beta and tau proteins in their spinal fluid. GWAS analyses identify gene regions that may be associated with disease by comparing patients to unaffected individuals to find areas where they differ; these DNA regions presumably have something to do with contributing to the disease in question. In this case, after matching up the symptoms of the Alzheimer’s patients with their genetic profiles, the scientists concluded that the genes they found, which coded for the receptors, influenced risk for Alzheimer’s by speeding up the progression of nerve and tissue damage. With more tau tangles, more nerves are compromised and cognitive functions start to decline.
The analysis revealed three genetic regions that are associated with tau formation, and that potentially provides Alzheimer’s researchers with new targets for diagnosing the disease early, as well as developing new treatments to combat the damaging effects of the protein. Previous GWAS analyses involved small numbers of patients, but the current studied included three times as many of those who are affected, which gives the authors more confidence that the new genetic regions are indeed important contributors to Alzheimer’s.
“This validated our whole method by saying yes you can identify genes that are likely influencing risk for developing Alzheimer’s disease by using this [method],” says Dr. Alison Goate of Washington University School of Medicine in St. Louis, and one of the study co-authors.
While it’s still unclear what triggers Alzheimer’s disease, experts believed that the build up of amyloid plaques were the primary contributor, with tau tangles following as the disease progressed. But Goate says that her results suggest there are genes that are independent of the amyloid mechanism that influence Alzheimer’s risk. “All of the other variants that have been studied so far — when we have understood the mechanisms — have involved amyloid-beta,” says Goate. ”Only one of the DNA variants [in this study] was associated with tau and [amyloid-]beta levels. All of the others show no association with amyloid-beta and only with tau, and that suggests there are mechanisms of risk for disease that are independent of the accumulation of amyloid.”
She is hopeful that by understanding these new pathways, it will be possible to identify new targets for treatment that could dissolve tau that might be used in combination with anti amyloid therapies, giving researcher a more multi-pronged approach in fighting the disease.
“Currently, there are a number of anti-amyloid-beta therapies in clinical trials, but it may be really helpful to have other drugs that target other components of the pathological cascade in Alzheimer’s disease,” says Goate. “As with any common complex disease, we would like to be targeting multiple components of the disease. In AIDS or in heart disease or in cancer, you don’t just go for one target. Usually people get drug cocktails, and within that cocktail, there are drugs that are targeting different pathways that lead to that disease. The idea here is that a drug could be developed that influences tau levels independent of amyloid-beta, and by reducing these levels, you likely reduce the risk of Alzheimer’s disease. The idea is to identify targets among these [genetic pathways] that could be modified by a drug that’s complementary to amyloid-beta therapy.” And with the latest estimates suggesting that Alzheimer’s is now the most expensive health condition in the U.S., costing up to $215 billion a year, such advances couldn’t come too soon.