One of the defining characteristics of Alzheimer’s disease is the presence of toxic amyloid plaques that build up in patients’ brains. Researchers have known that the protein apoE4 drives the growth of the plaques, but they haven’t been able to pinpoint at what stage it plays the most influential role. Knowing when to target apoE4—the protein produced from the apoE4 gene, which plays a role in more than 50 percent of late onset Alzheimer’s cases—may be a route to an effective treatment. In a paper published in Neuron, the lab of neuroscientist Guojun Bu, Ph.D., on Mayo Clinic’s campus in Florida, found that the apoE4 protein exerts its effect at the very beginning of plaque formation in the brain.
“We found apoE4 to have the greatest impact on amyloid formation during the initial, slow seeding period, as toxic proteins are first being deposited,” says Dr. Bu, the Mary Lowell Leary Professor of Medicine. The study followed the accumulation of amyloid plaque in mice, and found that as the plaques enter a stage of rapid growth with additional misfolded proteins, apoE4 becomes less critical. “ApoE4 protein has its effect early on, we believe by perturbing amyloid clearance and enhancing the aggregation of misfolded amyloid protein,” he says.
Interestingly, the findings from Dr. Bu’s lab concurred with another group at Washington University in St. Louis that explored the role of apoE4 by blocking the protein. The studies were conducted independently, and the two papers appear alongside each other in the journal. The findings underscore apoE4 as a target for drug intervention, and they also suggest that timing will be of the essence for an effective treatment. “Treatment targeting apoE4 may need to start early, in that seeding stage, even a decade or two before patients show symptoms,” Dr. Bu says. “Because we can test for the gene, and for additional biomarkers, this may not be difficult. A treatment that focuses on apoE4 ultimately would be preventative and would intervene before the plaque could form.”
Other Mayo Clinic researchers on Dr. Bu’s team are: Chia-Chen Liu, Ph.D., Na Zhao, M.D., Ph.D.,Yuan Fu, Ph.D., Na Wang, Cynthia Linares, and Chih-Wei Tsai. The study was supported by the National Institutes of Health, the Cure Alzheimer’s Fund, the BrightFocus Foundation, and the Alzheimer’s Association.