The State of Alzheimer’s Disease Genetics Research: A Discussion with Dr. Gerard Schellenberg

Highlights:

  • Human genetics helps us understand the biology of Alzheimer’s and identify drug targets.
  • Improvements in technology such as sequencing and gene therapy are promising.
  • Large sample sizes and rich phenotypes are critical to finding new AD genes.
  • Data visualization and outreach will encourage closer collaboration among the research community.

The University of Pennsylvania has been at the forefront of Alzheimer’s disease research for the last few decades. With efforts such as the Penn Neurodegeneration Genomics Center (PNGC), Center for Neurodegenerative Research (CNDR), and Institute of Aging (IOA), Penn is committed to rapidly advancing research in the field. A critical component of Alzheimer’s research is genetics. While it is clear that Alzheimer’s Disease and Related Dementias (ADRD) have a genetic component that contributes to onset and progression, the exact mechanisms and extent of genetic factors are less understood. I recently sat down with Dr. Gerard Schellenberg, Director of PNGC, to hear his thoughts on Alzheimer’s genetics research and where it is headed.

Genetics is critical in the field of Alzheimer’s research because obtaining information about the genetic causes of disease in a person translates directly to what AD researchers are looking for: genes that could serve as drug targets. “Drug targets that have genetic evidence supporting them as a candidate are two to three times more likely to succeed than drug targets that do not have genetic evidence,” Dr. Schellenberg notes. He also points out that we gain insights in completely unexpected mechanisms when looking at a disease that manifests in a person, instead of a cell culture, another advantage of studying human genetics. “It’s really just glimpsing nature without having to be that creative or even understand it,” he says, whimsically. Genetics also reduces preconceived bias. “The genetics tells you what you should be paying attention to rather than you picking out what you think is important and working on it.”

Currently, the Alzheimer’s disease research community “has solid information on 30-40 genes and preliminary information on another 20-30 genes,” Dr. Schellenberg says. New technology that changes monthly helps with genetic approaches; for example, increasing technology is making fundamental DNA sequencing cheaper and has allowed for the development of large genetic databases. “That’s going to broaden what we can look at”, Dr. Schellenberg says. Expression quantitative trait loci (EQTL) databases have become very large and useful, and Dr. Schellenberg explains that the use of this resource is happening here at the University of Pennsylvania. Gene therapy is another avenue for exploration. Dr. Schellenberg notes, “Gene therapy as a whole has been difficult, but I’m hoping they’ll turn a corner on using that.”

There is still a long way to go, however, in understanding the complete genetic architecture of the disease. A major aim going forward is increasing sample size in order to see rare variants. Dr. Schellenberg emphasizes, “The ability to detect something has to do with how rare it is but also its effect size.” Alzheimer’s cohorts such as the Alzheimer’s Disease Genetics Consortium (ADGC) are working to increase the ethnic diversity of studies so that we can discover genes that may have a larger effect in one population than another. Phenotypes also need to be harmonized, which is a laborious task.

Lastly, there is a great opportunity and need for creative outreach in the Alzheimer’s disease research community. The public should consistently be informed on progress and findings. Additionally, researchers and scientists would greatly benefit from increased sharing of data visualization tools and resources. “NIAGADS has a lot of tools now that are coming online and that allow people to visualize AD genetics,” Dr. Schellenberg explains.  If such collaborations can be developed further, research in the field may progress at a much higher rate.

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