CIRCUITS has its foundations in the Alzheimer’s Genome Project™ (AGP), headed by Rudy Tanzi, Ph.D., at Massachusetts General Hospital, and supported by Cure Alzheimer’s Fund since 2005. The AGP scanned the entire human genome from a large cohort of Alzheimer’s families for genes associated with risk for or protection against Alzheimer’s disease. The project identified dozens of risk genes, many of which currently are being investigated for therapeutic potential by CureAlz researchers.
“The AGP provided us with a wealth of genetic data,” explains Tanzi, “but to really understand how these genes are functioning in the disease, we need epigenetic data as well. That’s where CIRCUITS comes in.”
From Genetics to Epigenetics
Genes are sections of DNA that code for specific proteins. The APP gene, for instance, codes for the amyloid precursor protein. Mutations in these sections of code can lead to gain or loss of function as the mutated proteins perform differently than the typical version. Such changes can lead to dysfunction and disease in ways that, in many instances, scientists have been able to trace.
But recently, geneticists have found that genes themselves don’t tell the whole story. In addition to the genes in our DNA, there are vast sections of code that we are only just beginning to parse. Much of this DNA, which once was considered “junk,” is now thought to regulate whether and at what level genes are decoded into proteins.
“APP, APOE and other AD genes carry mutations that directly influence susceptibility to Alzheimer’s,” Tanzi explains, “but another section of DNA in the human genome might be responsible for regulating that gene. It’s just as important to understand this regulatory activity as it is to understand the gene defects themselves.”
These regulatory changes often take place through a process called DNA methylation. Molecules called methyl groups attach themselves to genes in DNA. The number and location of these groups will affect whether and how that section of DNA is made into proteins and used by the cell.
Epigenetics introduces new levels of complexity in our understanding of DNA, but also explains a great deal that our earlier concept of genetics could not. For instance, while an organism has the same DNA in each cell of its body, the location of methyl groups on the DNA can differ by cell type. This means that a neuron and a blood cell, for example, might have different patterns of methyl groups, and therefore identical genes produce different protein output in the different cell types. Additionally, evidence suggests that an organism’s life experience affects methylation, meaning how DNA is expressed can change over the course of an organism’s lifetime. As a result, two individuals born with the same gene variant impacting risk of disease still might face different levels of risk from that variant, depending on how their life experiences affect the methylation of that gene.
