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From the Farm to the Clinic, This Potamkin Prize Winner Has Made Research Inroads in Aging and Alzheimer's Disease

Article In Brief

Potamkin Prize recipient Randall J. Bateman, MD, FAAN, discusses his trajectory from life on a farm to leading major clinical trials in Alzheimer's disease.

Blame it on Snoopy and Baby Angus.

Growing up on his family's farm in Iberia, MO, Randall Bateman, MD, had a dog and his own pet cow.

“As I grew up, I got to see Snoopy and Baby Angus age,” said Dr. Bateman, the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University in St. Louis. “And all the other farm animals, from chickens to cows, horses and pigs—the different rates at which they aged just fascinated me. It seemed to me there must be something fundamentally genetic that drives the aging process. It became a lifelong interest.”

That interest prompted him to pursue research into Alzheimer's disease (AD). His work in the area was recognized in May at the AAN Annual Meeting when he was awarded the 2019 Potamkin Prize for Research in Pick's, Alzheimer's and Related Diseases. Sometimes called the Nobel Prize of Alzheimer's research, the Potamkin award and its $100,000 in prize money was given to Dr. Bateman in recognition of methods he developed with colleagues to measure de novo synthesis of amyloid-beta (Abeta).

Using the method, known as stable isotope labeling kinetics (SILK), he and colleagues have shown that clearance of Abeta is slower in the brains of people with AD than in controls. [See “The Science Explained-Stable Isotope Labeling Kinetics:”]

The Mentors

In an interview with Neurology Today from University College London, where he was on sabbatical, Dr. Bateman credited much of his success to his two mentors, both of whom have long since become colleagues at Washington University: John C. Morris, MD, FAAN, the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology, and David M. Holtzman, MD, FAAN, the Andrew B. and Gretchen P. Jones Professor and chair of the department of neurology.

“One day, when Dave was my attending, he and I were having lunch in the residents' cafeteria area,” Dr. Bateman recalled. “They had this massive pot of soup with rolls. Year after year, it never changed: a different soup but the same rolls every day. We sat there eating our soup and rolls, talking about science. He showed me a paper of his on a mouse model of AD, and how treating the mouse with an antibody could stop the pathology from developing. I was completely amazed by that. I remember asking, ‘Now that you've figured out how to stop the pathology, isn't the disease all but cured? Maybe the field doesn't need more researchers to go into it.’ Dave just chuckled.”

Another time, Dr. Bateman recalled, he asked Dr. Holtzman why plaques form in the brains of people with AD: because they make too much Abeta, or because they clear it too slowly?

“It was unusual for Dave to take a while to answer,” Dr. Bateman said. “Finally he told me he didn't know but asked how that question could even be addressed. From that question, I began brainstorming ways to figure out the answer.”

Research on Abeta

His first grant proposal outlined his attempt to do just that, “but the reviewers wrote back that it was a terrible idea and it couldn't work,” Dr. Bateman said. “They gave me all the scientific reasons why it wouldn't work, which made me angry. In retrospect, of course, it could very well have not worked. It was a real shot in the dark. Luckily, amyloid-beta's turnover rate is fast enough that we could measure it.”

Prior to the development of SILK, scientists did not know whether sporadic AD is associated with overproduction of Abeta, or insufficient clearance of it. The technique developed by Dr. Bateman, Dr. Holtzman, and colleagues began with administration of a stable carbon isotope of the essential amino acid leucine, which tagged all the newly made Abeta present in the CSF. Then, by repeatedly measuring how much of the tagged Abeta remained in the hours following, they demonstrated that in healthy subjects, 7.6 percent of Abeta in the CNS is newly produced each hour, while 8.3 percent is cleared.

The results of the study that early reviewers told him would never work were published in 2006 in Nature Medicine.

The original technique, however, was time-consuming and difficult for patients to tolerate. CSF had to be collected for 36 hours in the clinic, and two of the 10 patients enrolled in the original trial dropped out because they developed headaches following lumbar punctures.

As a result, Dr. Bateman and many other teams have since worked to develop a reliable blood test of Abeta. In 2017, his group reported the first highly accurate blood plasma test of Abeta.

They again used the SILK technique, but this time it was applied to three different stable isotopes of Abeta—Abeta 38, Abeta 40, and Abeta 42—and also measured the concentrations. The latter, they found, had a turnover rate in plasma similar to that previously observed in CSF and the concentration of Abeta 42 to Abeta 40 was highly specific for identifying amyloid plaques in the brain.

“The stability and sensitivity of plasma Abeta measurements suggest this may be a useful screening test for central nervous system amyloidosis,” the 2017 study Dr. Bateman coauthored in Alzheimer's & Dementia concluded.

“A specific blood test for Alzheimer's disease amyloid plaques is changing how we do research in this area,” Dr. Bateman said, “and it may also change how we work in the clinic. We've had spinal tests and PET scans, but those were perceived to be expensive and invasive. A simple, single blood test is what we have needed from a diagnostic standpoint.”

What the Future Portends

Looking forward, Dr. Bateman said he is particularly excited about primary and secondary prevention studies involving the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU), which he founded.

“Our DIAN-TU trial is going to read out the first prevention trial results with two drugs, gantenerumab and solanezumab, in early 2020,” he said. “Those will give us the first glimpse of what happens when you try to treat the disease years before it becomes clinically apparent.”

Aside from agents targeting Abeta, he said, “The tau-based trials have incredible promise for symptomatic treatment. I'm also excited about efforts to target the microglia and the immune system. Genetic treatments that target protein expression could also have a massive clinical effect, which is what we need.”

Dr. Bateman said his mother and father both still live on the farm where he grew up, as does his brother. Although he visits there a few times every year, “I stay away from bucking hay and shoveling manure,” he said. “Farm work is hard and I'm not very good at it. I went into academics for a reason.”

Link Up for More Information

• Bateman RJ, Munsell LY, Morris JC, et al. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo Nat Med 2006;12(7):856–861.
• Ovod V, Ramsey KN, Mawuenyega KG, et al. Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis Alzheimers Dement 2017;13(8):841–849.