Members of the Charlottesville community gathered at the Jefferson-Madison Regional Library Sunday for the semester kickoff of the “U Ask, U.Va. Answers” speaker series. Asst. Prof. of Neuroscience Dr. Sarah Flowers spoke at Sunday’s session about her research into the genetic risk factors and therapies behind Alzheimer’s disease.
The “U Ask, U.Va. Answers” speaker series is hosted by the Office of the Vice President for Research with the goal of presenting University research to the Charlottesville community and sparking curiosity in the public.
A type of dementia, Alzheimer’s disease is a progressive brain disorder characterized by memory loss and an eventual inability to complete everyday functions. In the brain, Alzheimer’s disease manifests as the accumulation of amyloid-beta plaques and tau tangles, which then disrupt intracellular communication and cause irreversible neuronal death.
In contrast to most other cells throughout the human body, neurons — responsible for communicating and processing signals in the nervous system — cannot regenerate once they have died.
In her research, Flowers looks at the pathology of early Alzheimer’s disease and how changes in metabolism and carbohydrate-based protein modifications impact neurodegeneration.
According to Flowers, Alzheimer’s disease is currently the sixth-leading cause of death in the United States, and the population of people affected by the disease is projected to almost double by 2060. She added that the goal of her lab is to discover methods to halt the pathology of Alzheimer’s disease before the accumulation of tau tangles and amyloid plaques.
“If we can catch [early signs of Alzheimer’s disease], we can treat somebody before they get amyloid, before they get tau, we could stop the progression to Alzheimer’s disease,” Flowers said. “[The question is if we can] make that brain hold its resilience so that it can stave off those pathologies longer and longer and longer until we never ever see [the signs] of Alzheimer’s.”
A major focus of her work is glycosylation, or the process of attaching specific carbohydrate groups to proteins or lipids, and she studies how it affects the function of the Apolipoprotein E protein, which transports cholesterol in the brain. Certain variants of the APOE gene remain one of the strongest genetic risk factors for Alzheimer’s disease, impacting more than 50 percent of all cases.
There are three main forms of the ApoE protein — ApoE2, ApoE3 and ApoE4. The ApoE4 allele is considered a risk factor for Alzheimer’s disease, with 25 percent of the population having one copy of the variant out of each individual’s two alleles. Two copies of the ApoE4 allele are present in 2 to 3 percent of people. ApoE3 is considered a neutral variant, and the gene form the most common of the three in the U.S., and ApoE2 is a protective variant against Alzheimer’s disease. ApoE2 is the most rare of the three variants — according to Flowers, around 5 percent of the U.S. population possess one copy of ApoE2 and less than 1 percent of the U.S. population has two copies.
Currently, Flowers’ lab is working on two aspects of Alzheimer’s disease — detecting the warning signs for disease pathology and developing therapeutics to manage the symptoms of neurodegeneration after they appear. According to Flowers, one potential treatment for harmful protein accumulation as a result of Alzheimer’s disease that has shown promise is benfotiamine, a synthetic derivative of vitamin B1.
“The reason that thiamine, or vitamin B1, is essential is because it keeps our cells active,” Flowers said. “It makes sure that we’re converting our glucose into energy, [and] if it’s not there, we stop being able to do that.”
She recently conducted a clinical patient trial alongside researchers at Cornell University, in which people at the early stages of Alzheimer's disease were given benfotiamine as a treatment. For subjects with ApoE3 genotypes, as compared to patients given a placebo drug, treatment with benfotiamine stopped progression of cognitive impairment. However, according to Flowers, benfotiamine did not have any significant impact on patients with ApoE4 genotypes.
Flowers said that despite the disappointment from the results of the ApoE4 trials, a novel takeaway from the clinical trial was that targeting metabolism could benefit Alzheimer’s disease. Currently, she is working on a larger study to examine the effects of benfotiamine on cognitive ability in patients with Alzheimer’s disease taking place in 46 hospitals across the United States and Canada with hundreds of patients.
According to Flowers, the benfotiamine treatment may have failed to impact ApoE4 patients because of genetic differences causing changes in metabolism significant enough to impact patient results. Her laboratory is currently using cell models to uncover some of these differences between cells with ApoE4 and others, as well as testing drugs with different pathways of impact to greater influence ApoE4 patients.
Flowers is also investigating the changes in the ApoE proteins over a lifetime that might result in the development of Alzheimer’s disease.
“You’re born producing ApoE4, that doesn’t change,” Flowers said. “But people aren’t getting Alzheimer’s when they’re 10 or when they’re 20 or when they’re 50 … but the ApoE has always been ApoE. So what’s changing?”
She cited glycosylation as the root of the change, which can modify the functions of the proteins without changing the genetically-derived structure of the protein itself. In her research, she found that glycosylation of the ApoE proteins changes in patients with Alzheimer’s disease. In these patients, the amount of functional glycosylated ApoE in the bloodstream is reduced by about half.
As a result of her findings that the quantity of glyco-ApoE changes in patients with Alzheimer’s, Flowers is currently working with the Virginia Alzheimer’s Disease Center research registry to collect blood samples and further investigate potential insights into the disease. Flowers also said that it was important to note that having a certain variant of the ApoE gene is a risk factor, not a diagnosis.
“Diseases are caused by our genetics and our environment, and that’s a massive interplay,” Flowers said. “And so the toxins, air pollution, is definitely one. Air pollution, especially as we get older, has a big impact on us. It increases our risk of Alzheimer’s disease.”
She also cited factors that decrease risk of Alzheimer’s disease — increasing exercise, getting enough sleep, keeping blood sugar levels constant and preventing things like hearing loss and social isolation.
Catherine West, director of communications for the Office of the Vice President for Research, said that the goal for the speaker series was to make science accessible to the public.
“We like to think about the topics that are most interesting for the community, and we actually worked with the library last year to talk to their audience. Alzheimer’s, for example, was one that was very highly requested,” West said.
West said that she looks forward to expanding the reach of the program further into the community.
“This was a wonderful kickoff, and the hope for this program is to bring it to more libraries … I think we have seen our attendance steadily grow, so we’re happy that the community is finding these things useful,” West said.
The next “U Ask, U.Va. Answers” event will take place Oct. 11 at the Jefferson-Madison Regional Library’s Central Library, featuring Bryan Berger speaking about his research on biotechnological innovations for food quality and safety.
Charlotte Gabriel is a second-year Commerce and College student, and she serves as a staff writer on the news desk.
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