Finding those answers lured Wilcock and Dage to IU School of Medicine. Their arrival added even more depth to an abundant bench of talented researchers in neurodegenerative disorders. Advances in diagnosing and treating Alzheimer’s have taken time, but that progress is rapid compared to work in vascular dementia, Lewy body disease, and Parkinson’s disease.
“That’s what I was brought here for,” said Wilcock, who earlier this year uprooted her lab from the University of Kentucky’s Sanders-Brown Center on Aging. “I want us finding and validating biomarkers for all the other dementia-causing pathologies.”
For Dage, the journey to IU was much shorter, barely a mile from Lilly’s corporate and research hub. Despite the proximity, Dage admitted he “didn’t really have a full appreciation for the nature of the work that’s going on” at IU.
Clarity came when he needed samples for a project related to rare neurodegenerative disorders known as frontotemporal dementia. Dage reached out to an NIH-backed repository at IU, the nation’s largest biobank for dementia. During Dage’s conversations with Tatiana Foroud, PhD, who oversees the facility, talk turned to the possibility of Dage helping set up a biomarker lab.
Lilly agreed to cover 10 percent of his time to work on the project, but Dage quickly realized it was far too small. To pursue the project and innovative work would mean leaving the pharmaceutical giant, which he did in 2021. Moving to the School of Medicine "was an opportunity to blaze a new path for myself," he said.
THE BLOOD TEST Dage helped design might serve as a template for discovering biomarkers for other diseases. But in 2014, his idea to look in blood for a biomarker of a disease occurring in the brain was met with skepticism. Then, Dage's team at Lilly needed biomarkers to test the potential of drugs to act on a target. That search led them to an intriguing protein: phosphorylated tau.
Set aside all the syllables and think of tau this way: cargo transport. Neurons in our brain have cell bodies, a long axon, and synapses at the end. Those synapses—and the signals they fire off—regulate our memory, motor skills, and behavior. To keep that network online, neurons ship proteins from one end to the other. T
au acts to facilitate the shipping service, passing those packages along. It also needs a place to anchor for stability, which is done at phosphorylation sites, giving us the moniker “p-tau.” But those proteins can get stuck and misfolded, creating snags that grow into the trademark tangles in Alzheimer's.
Eventually, those tangles block the shipping lane, stressing neurons to the point they die. When that happens, tangles are chopped up and excreted. Faint traces filter into the bloodstream.
So, what makes Dage’s version unique? The antibodies it uses don't occur naturally: They were designed for this specific purpose. "We really spent a lot of time engineering those tools to make the test what it is," Dage said. To test its performance, the drug company partnered with several academic institutions around the world, led by the Mayo Clinic in Rochester, Minnesota, Lund University in Sweden and University of California, San Francisco.