Researchers have identified genetic processes that are involved in the neurodegeneration that occurs in dementia. Appearing today in Nature Medicine, these findings are an important step toward developing therapies that could slow or halt the disease.
The research team discovered two major groups of genes involved in mutations that result in an overproduction of a protein called tau—a hallmark of the progressive loss of neurons seen in major forms of dementia. The study was largely done in mouse models of dementia, although the researchers performed additional experiments that indicated that the same genetic process occurs in human brains.
Armed with this knowledge, the team searched a large database of the genetic effects of experimental drugs to identify those that might affect neurodegeneration and tested them in human cell cultures.
"Our study is the most comprehensive published effort to date to identify the source of neurodegeneration across species and provides an important roadmap for the development of potentially effective new drugs for Alzheimer's disease and other dementia," says senior author Daniel Geschwind of UCLA.
Although scientists have identified genes associated with dementia risk, there is little understanding of how those genes contribute to the cascade of events that lead brain cells to die.
Using an approach called “systems biology,” the researchers identified genetic processes in a mutation that results in the overproduction of tau in frontotemporal dementia—a form of early-onset dementia. A similar process also has been shown to play an important role in Alzheimer's disease and another form of dementia known as supranuclear palsy, which affects both movement and cognition.
Geschwind's team hypothesized that one reason why research with mouse models of dementia often fails to produce results that are translatable to humans is that most mouse studies have relied on a single inbred strain. To increase the likelihood that their findings would have broader implications, the researchers studied the mutation caused by frontotemporal dementia in three genetically distinct strains of mice. They found two gene clusters that were associated with neurodegeneration across all three mouse models in the susceptible regions of the brain.