The complexity of the human genome is extremely high. Even with today’s high-tech sequencing instrumentation, about one-quarter of the human genome is incompletely sequenced. Specifically, genomic regions with repeated elements are challenging to sequence using current technology. Many researchers, including the University of Kentucky’s Peter Nelson, think these “hidden” genomic regions may be key to understanding Alzheimer’s disease, especially the genes that influence the neurodegenerative disease’s high heritability.
Although Alzheimer's is known to be largely heritable, researchers recognize there is a knowledge gap when it comes to heritability. For example, while heritability explained 79 percent of late-onset Alzheimer disease risk in a Swedish twin study, common risk variants identified by previous genetic studies explained only 20 to 50 percent of late-onset Alzheimer disease. In other words, a relatively large amount of genetic influence on late-onset Alzheimer disease risk was not explained by prior genetic studies.
“There is a lot of unexplained genetic influence of Alzheimer’s disease that remains to be characterized,” Nelson told Laboratory Equipment. “This [study] helps to fill that donut hole.”
Nelson’s most recent study, published in the Journal of Neuropathology & Experimental Neurology, was a two-step research study utilizing sequencing and digital pathology. Nelson and his co-author Yuriko Katsumata conducted a whole genome-wide screen of 10,000 people looking for variants that distinguished those with Alzheimer’s versus controls. During the screening, the gene Mucin 6 (MUC6) jumped out at the researchers, who then tested a smaller group of participants to try to get closer to the gene.
“We used very quantitative metrics of human brain pathology to try to see if there were changes in that region that were associated with the pathology of the brain that is associated with Alzheimer’s in turn,” Nelson explained. “And there were. The correlation was pretty strong even though there weren’t that many in the sample size—only about 293, about half of which were Alzheimer’s, half not.”
Although preliminary in nature, study results showed the size of the MUC6 variable number tandem repeat (VNTR) region was associated with pTau pathologic burden in the neocortex. Additionally, larger MUC6 VNTR regions were also associated with decreased AP2A2 expression in human brain tissue. The researchers hypothesize that dysregulation of AP2A2—a protein-coding gene—is associated with pTau proteinopathy in late-onset Alzheimer’s disease, and suggest the gene as a further area of research.
“Every time you understand a new gene that is associated with a disease, it tells you something very strong about what causes that disease,” Nelson said. “The molecular pathway involved, how we can diagnose a disease, and hopefully, ultimately, it provides therapeutic targets. In order to be able to ultimately combat genetic influence, we need to identify and then generate therapeutic strategies for turning an unhealthy person into a healthy person.”
Nelson said Alzheimer’s disease is interesting to study because it’s not inevitable—20 percent of people who are 90 years old show no signs of the neurodegeneration.
“That is evidence that we could slightly tilt the equilibrium toward the forces that enable us to beat the disease,” he said.
Nelson and his colleagues at the University of Kentucky Alzheimer’s Disease Center are continuing their research to more specifically determine the sequence elements that lead to the disease in a bid to generate possible therapeutic strategies and alternatives.
“There is a lot to be learned, and hopefully this study will fill a substantial hole,” he said. “But the big picture is we have a lot of wood to chop.”
Photo: Anti-MUC6 antibodies