Dementia results in decline of the memory and other cognitive functions. While Alzheimer’s accounts for up to 80 percent of dementia cases, there are other causes as well, including vascular dementia post-stroke, thyroid and vitamin deficiencies. Things sure do start small with dementia but eventually result in drastic changes in the quality of life.
Advances in high-throughput whole genome sequencing had led to a dynamic shift in understanding the genetics associated with neurodegenerative diseases. Genetic factors have been recognized as a critical contributor for dementia and identifying these genes will eventually allow for gene-specific therapeutics to be developed. 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.
The research team sought to solve that puzzle through an approach known as "systems biology," which applies powerful genomic and analytic tools to studying the genome holistically, taking into account the complex interactions of the thousands of genes and the cells and proteins they produce.
A UCLA-led research team has identified genetic processes involved in the neurodegeneration that occurs in dementia—an essential step on the path toward developing therapies that could slow or halt the course of the disease. The findings appear on December 3rd in the journal Nature Medicine.
The researchers discovered two significant 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 significant forms of dementia. The study was primarily done in mouse models of dementia, although the researchers performed additional experiments that indicated the same genetic process occurs in human brains.
Brain scan of dementia patient shows neurons with Tau protein (in green) and reactive astrocyte cells (in red). Credit: UCLA/Geschwind lab
Armed with that knowledge, the team searched an extensive database of the genetic effects of experimental drugs to identify those that might alter this loss of neurons or neurodegeneration. In human cell cultures, the researchers showed that the use of these molecules interfered with neurodegeneration.
"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," said senior author Dr. Daniel Geschwind, a professor of neurology and psychiatry who holds the Gordon and Virginia MacDonald Distinguished Chair in Human Genetics at the David Geffen School of Medicine at UCLA.
The researchers used systems biology to identify 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 essential role in Alzheimer's disease and another type of dementia known as supranuclear palsy, which affects both movement and cognition.
Geschwind's team hypothesized that a reason why research with mouse models of dementia often fails to produce results 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. The team looked at the genetic activity occurring in different parts of and points of time in a degenerating brain.
In the study, two gene clusters were found to be associated with neurodegeneration across all three mouse models and in the susceptible regions of the brain.
"There is still a significant amount of work that needs to be done to develop drugs that could be effectively used in humans against these targets, but this is an encouraging step," said Geschwind, who also serves as co-director of the Center for Neurobehavioral Genetics at the Semel Institute for Neuroscience and Human Behavior at UCLA, and senior associate dean and associate vice chancellor of precision medicine at UCLA Health.