W.M. Keck Foundation awards $1.2 million to KU team pursuing new theory of Alzheimer’s disease

LAWRENCE — What if our current understanding of Alzheimer’s disease is incorrect?

A research team led by a University of Kansas School of Pharmacy professor is trying to answer that question with a $1.2 million grant awarded by the W.M. Keck Foundation. The team’s novel hypothesis could explain why existing treatments only modestly slow the rate of cognitive decline, and in doing so, lead to newer, more effective treatments.

Michael Wolfe, interim department chair and Mathias P. Mertes Professor of Medicinal Chemistry, will lead the project along with KU collaborators Brian Ackley, professor of molecular biosciences and co-director of the undergraduate biology program, and Jesse Wiley, associate professor of pharmacology & toxicology. Kim Green, a Chancellor’s Professor and vice chair in the department of neurobiology & behavior at the University of California, Irvine, is also a co-investigator.

Challenging conventional wisdom

The prevailing view of Alzheimer’s disease (AD) posits that cognitive decline associated with the illness is caused by a buildup of brain plaque first observed by Alois Alzheimer in 1906. Scientists determined in the 1990s that this plaque is composed of amyloid-β peptide, and efforts to treat the disease have centered on removing or preventing the buildup of this plaque.

“You treat patients over the course of a few months with these anti-amyloid agents and the plaques disappear. But the effects are equivocal — they only modestly slow the rate of cognitive decline on average,” Wolfe said.

“At this stage, it could be argued that clearing amyloid does not have a profound effect on slowing the rate of cognitive decline.”

Wolfe and his colleagues wondered if excess amyloid found in the brain was only a sign, rather than the cause, of AD. For the past several years, they have focused on a new potential culprit: slowing or stalling of the enzyme that creates amyloid. This enzyme, called gamma-secretase, normally cuts long proteins into smaller fragments that play important roles in healthy brain function. But mutations associated with early-onset familial Alzheimer’s disease appear to slow the enzyme’s activity, causing it to stall during one or more of the multiple processing steps it normally completes in healthy cells.

“No one had ever looked at the effects of these mutations that cause Alzheimer’s disease on all of those cuts,” Wolfe said. “Everybody just concentrated on the secreted final products.”   

To test whether the stalled enzyme hypothesis better explains Alzheimer’s disease than the prevailing amyloid hypothesis, Wolfe and his colleagues will leverage funding from the W.M. Keck Foundation to conduct experiments in roundworms, mice and human neurons grown in laboratory dishes. Using gene editing, the researchers will create one set of organisms or cells that contains stalled enzymes but do not produce excess amyloids and another set that contains stalled enzymes and produces amyloids. Comparing the two groups could help determine whether stalled enzymes, rather than amyloid buildup, drive disease-related changes in the brain.

Driving discovery through collaboration

Wolfe said both a culture of collaboration and KU’s strategic investments in research infrastructure were integral to earning this grant. Preliminary data derived from earlier studies came from an existing partnership between Wolfe and Ackley that spans the past five years.

“We’ve published a couple of papers together that provided the first in vivo evidence,” Wolfe said.

Conducting research in a university setting also opens research experiences to students, jump-starting their careers and lending fresh perspectives to projects. Incoming KU graduate student Parnian Arafi began working in Wolfe’s lab as a freshman undergraduate student four years ago, and her contributions have helped the team advance its hypothesis.

“Parnian ended up getting important additional evidence for this hypothesis,” Wolfe said. “She was the lead author on a paper that we published.”

Wiley, whose lab will conduct the cultured human neuron experiments, was hired last academic year as part of Research Rising, a five-year KU initiative investing more than $12 million in four interdisciplinary projects working to address critical challenges facing humanity. Wolfe leads the Research Rising project focused on using big data to improve drug discovery.

“We were very fortunate that Jesse Wiley does research in the area of Alzheimer’s disease and was excited to come here and start working on this new amyloid-independent hypothesis, along with his own ideas,” Wolfe said.

These opportunities for collaboration are what brought Wolfe back to Lawrence. After completing his doctorate at KU, he embarked on a scholarly career that eventually led to a faculty position at an Ivy League school. But Wolfe said he recognized that KU offered the collaborative environment his work needed to advance.

“Coming back, I had new opportunities to collaborate and identify people who were more willing to question the amyloid hypothesis,” he said. “I would say we would not have discovered these things had I not come back to KU.”

Funding high-risk, high-reward ideas

Pursuing unconventional ideas often requires alternative sources of support. Philanthropic funders can play a critical role in advancing research that federal agencies and private industry may consider too speculative or early-stage. Wolfe said the W.M. Keck Foundation grant will help his team generate the evidence needed to secure future support for research on the stalled enzyme hypothesis. 

“I had one reviewer at a federal agency say, ‘This is deviant Alzheimer’s research,’” Wolfe said. “If we turn out to be right, that’s going to be something that’s plastered on slides I present about this work.” 

About the W.M. Keck Foundation

The W.M. Keck Foundation was established in 1954 in Los Angeles by William Myron Keck, founder of The Superior Oil Company. One of the nation's largest philanthropic organizations, the W.M. Keck Foundation supports outstanding science, engineering and medical research. The foundation also supports undergraduate education and maintains a program within Southern California to support arts and culture, education, health and community service projects.

About KU Endowment

KU Endowment is the independent, nonprofit organization serving as the official fundraising and fund-management organization for KU. Founded in 1891, KU Endowment was the first foundation of its kind at a U.S. public university.