The Alzheimer’s Association has long argued for more funding for prevention or slowing down progression of the disease that affects cognitive functioning of ten percent of Americans 65 and older, and one out of three 85 and older. With the aging Baby Boomer population, current Medicare and Medicaid costs for care of people with this memory-robbing disease, currently estimated at $186 billion per year, are expected to increase to $750 billion by 2050.
The emotional toll of Alzheimer’s affects all those who love and care for those with AD.
My father, L.A. Gillette, Jr., was a major figure in the Idaho potato industry. I remember him traveling to Washington D.C., to meet with Sen. Frank Church to lobby for putting a tax on Idaho potatoes in order to trademark and market them as Famous Idaho Potatoes. Before that, Idaho potatoes weren’t famous.
Dad, a survivor of a Nazi World War II concentration camp, was one of the more influential farmers in the state for many years. But from his mid-70s until he died at 87, he was increasingly unable to care for his most basic needs. He struggled with confusion, fear, and anxiety. Around the same time and in years since, I have seen elders on both sides of my family, as well as dear friends, struggle with AD.
These experiences left me with a keen interest in Alzheimer’s research and funding. I’ve read about how a good diet, avoidance of toxins and excessive alcohol intake, exercise, and healthy social relationships can help prevent AD and other forms of dementia. But by the time this disease is apparent, it can be too late to shift the outcome.
Recent research, by a team headed by Sue Griffin, Ph.D., University of Arkansas for Medical Sciences (UAMS) in Communications Biology, made an exciting discovery with the potential to be a true game changer for the estimated 50 to 65 percent of people who have inherited the Alzheimer’s gene, Apolipoprotein E4 (APOEε4), from one or both parents. The 25 percent of people with AD who have one copy of APOEε4 are three times as likely to develop the disease. Those with two copies (one from each parent), are 12-15 times as likely to develop Alzheimer’s.
Griffin said her team appears to be the first with this new drug-related discovery, just as it was the first in 2018 to show how APOEε4 prevented brain cells from disposing of their waste products, known as lysosomal autophagy. She said such disruption of autophagy in those who inherit APOEε4 is responsible for the formation of plaques and tangles in the brain that are hallmarks of AD. That groundbreaking discovery was published in Alzheimer’s and Dementia, the journal of the Alzheimer’s Association.
“Our series of discoveries related to APOEε4 and its detrimental role in Alzheimer’s pathogenesis are among the most impactful of my fifty years as a research scientist,” Griffin, a pioneer in the study of neuroinflammation and co-founder of the Journal of Neuroinflammation, said. “No other research team has found a potential drug specifically for blocking the harmful effects of inherited APOEε4.”
The UAMS press release said most national Alzheimer’s research has focused on treatments that can clear away the brain’s plaques and tangles associated with the disease, but that approach has not been impressive. Griffin said that people with mild Alzheimer’s symptoms have already lost about half or more of the neurons responsible for memory and reasoning, which led to her and her team to focus on prevention.
Griffin’s team is advancing its innovative work with a recent five-year, $2.35 million grant from the National Institutes of Health. The team will conduct larger-scale preclinical research on the drug candidate, CBA2, as well as test other potential drug candidates.
“Our hope is that people who have one or two copies of APOEε4 will one day take the drug regularly throughout their life and significantly reduce their risk of developing AD,” Griffin said.
Meenakshisundaram Balasubramaniam, co-principal investigator on the NIH grant with Griffin, said UAMS built the first known full-length structure of APOEε4 protein in 2017, which he created using bioinformatics and computational modeling techniques. This foundational work led to the discovery of the druggable site on the APOEε4 protein, ApoE4. Balasubramaniam’s unique skills and curiosity, Griffin said, were the catalyst for the discoveries.
“I don’t know of anyone else in the world but Dr. Balasubramaniam who can do the work that’s in this paper,” Griffin said of the assistant professor and Inglewood Scholar in the Department of Geriatrics. While most institutions still manually screen drug compounds, which can take years, Balasubramaniam oversees a computational biology suite with high-performance GPU servers that he used to screen about 800,000 compounds in two days.
A provisional patent has been awarded on the CBA2 drug candidate, and full patent approval is pending.
The collaborating researchers include Srinivas Ayyadevara, Ph.D., associate professor, Department of Geriatrics; Steve W. Barger, Ph.D., professor, departments of Geriatrics, Neurobiology and Developmental Sciences, and Internal Medicine; Peter Crooks, Ph.D., D.Sc., professor, College of Pharmacy Department of Pharmaceutical Sciences, Simmons Chair in Cancer Research; and Robert J.S. Reis, Ph.D., professor, departments of Geriatrics, Biochemistry and Molecular Biology, and Pharmacology and Toxicology.