Ongoing research across CU Anschutz Medical Campus could shed light on potential connection
Recent findings linking COVID-19 and Alzheimer’s disease have sparked concern among experts, taking the spotlight at the July Alzheimer’s Association International Conference in Denver and prompting an “urgent” call from the Alzheimer’s Disease International for “fast-tracking” research on the issue.
Emphasizing that a connection between the two illnesses is far from clear, experts in the field at the University of Anschutz Medical Campus agree the news is “worrisome,” given the magnitude of the potential fallout.
“It’s urgent because COVID-19 is a pandemic that is affecting millions of people throughout the world,” said Huntington Potter, PhD, director of the University of Colorado Alzheimer’s and Cognition Center and professor of neurology. “If it increases the risk of Alzheimer’s disease, then that could be another pandemic catastrophe in the making.”
Adding to a healthcare crisis
Already a burden on the nation, dementias cost $355 billion a year, tax the healthcare system and upend the lives of the 6 million Americans living with the disease and their caregivers. As people live longer, experts predict those numbers will more than double in the next 30 years.
“That’s been a concern for a long time now,” said Brianne Bettcher, PhD, a clinical researcher at the CU School of Medicine’s Alzheimer’s and Cognition Center, who called recently publicized studies linking COVID and Alzheimer’s “certainly worrisome. You add on a pretty massive risk factor (like COVID) … and I think that there is a lot of urgency.”
Did you know? The loss of taste and smell as early signs
of COVID-19 are not unique to the disease, occurring with
other viral infections – and with Alzheimer’s disease?
CU Anschutz researcher Diego Restrepo, PhD, and
Bettcher recently received a National Institutes of Health grant to study the similarities between the two diseases.
Translating research to find answers
Since the first COVID-19 case hit the state, CU Anschutz researchers joined minds in unraveling the mysteries of the novel SARS-CoV-2 virus responsible for 4.7 million deaths and 231 million confirmed COVID-19 cases worldwide. Their work sheds light on the potential connections between COVID and Alzheimer’s disease, the top cause of dementia in the country.
Neurological effects strike some patients with COVID-19, including dizziness, brain fog and confusion. Early studies, including one by Thomas Wisniewski, MD, and colleagues at New York University, have discovered hallmarks of Alzheimer’s disease, such as loss of smell and blood biomarkers (notably UCH-L1 and tau), in some COVID cases.
At the Linda Crnic Institute for Down Syndrome on campus, researchers focus on understanding the neurological effects of hyperinflammation, which can be a common factor across Down syndrome, COVID-19 and Alzheimer’s disease, said director and Professor of Pharmacology Joaquin Espinosa, PhD.
People with Down syndrome have a markedly increased risk of Alzheimer’s and the highest risk of any group for severe COVID-19 and death, he said.
“The question is then, what are the mechanisms by which a viral infection can somehow lead to brain damage that is similar to mechanisms in Alzheimer’s and Down syndrome?” Espinosa said. Some answers likely lie within the inflammation process, which can lead to damage of the endothelial cells that line the blood vessels and control immune and blood-clotting properties, among other things.
“If you have brain damage during severe COVID or Long COVID, yes, your blood will have some of the same biomarkers that are observed in people who have brain damage due to Alzheimer’s disease,” he said.
Finding a potential pathway
Espinosa and colleagues have zeroed in on the kynurenine pathway, which can be activated during inflammation and lead to production of neurotoxic compounds, such as quinolinic acid, otherwise known as the “inescapable neurotoxin.”
The activated pathway also depletes serotonin, a key neurotransmitter involved in mood control, leading to depression, Espinosa said.
In Alzheimer’s disease, the amount of kynurenine activation and the amount of quinolinic acid production has been tied to more severe disease.
“We were the first to demonstrate that the kynurenine pathway is activated in Down syndrome,” Espinosa said of his lab. “And then another team last year led by Angelo D’Alessandro in the Department of Biochemistry and Molecular Genetics was the first to demonstrate that this pathway is also activated in COVID-19,” Espinosa said.
“That won’t give you Alzheimer’s overnight, but it may cause brain damage that may predispose you farther down the road to Alzheimer’s disease.”
Other forms of brain damage increase Alzheimer’s risk, including traumatic brain injury, Espinosa said.
Discovering preventive therapies
Promising research in Potter’s lab investigating GM-CSF (Granulocyte-Macrophage Colony Stimulating Factor), marketed as Leukine, as a treatment for Alzheimer’s, could translate into a brain-protective therapy with COVID infection.
Potter’s team, whose clinical trials on Leukine for Alzheimer’s disease are underway at CU Anschutz, is looking at the therapy’s potential to reduce mortality and brain damage in a mouse model of COVID-19.
GM-CSF increases the body’s innate immune response by boosting activation of macrophages and microglia, the phagocytes or “little Pac-Men that go around and eat up things that are not supposed to be there,” Potter said.
“That is one of the reasons why we think that GM-CSF is beneficial in Alzheimer’s disease. It activates these phagocytes, and they eat up the amyloid and the amyloid beta peptides.”
“If it increases the risk of Alzheimer’s disease, then that
could be another pandemic catastrophe in the making.”
– Huntington Potter, PhD, on COVID-19
GM-CSF has also been shown to help make new nerve cells and blood vessels and keep nerve cells from dying, counteracting the effects of hyperinflammation, Potter said. It can also help the body mount an adaptive immune system, where it makes antibodies to get rid of the virus, he said.
“So, all in all, it’s a very good natural protein that the body makes all by itself, but if we give more of it, we think it’s going to help get rid of viruses earlier than the body could do by itself,” he said.
Transferring findings to fuel others
“GM-CSF actually does a lot of beneficial things for the brain,” said Potter, whose early studies with the laboratory of Kenneth Tyler, MD, professor of neurology, are also investigating the therapy’s effects on West Nile virus. “We are very excited about the potential for early treatment of viral disease.”
A drug that Espinosa’s lab has long studied and is used to tone down the immune system in Down syndrome is showing great promise in the treatment of COVID-19.
Baricitinib, which belongs to a class of molecules known as JAK inhibitors, was recently given emergency use authorization for COVID by the Food and Drug Administration.
“The latest clinical trial showed the strongest effect than any other medicine, shortening hospitalizations and reducing mortality by 44%,” Espinosa said.
Targeting COVID-19 pandemic’s fallout
In Bettcher’s lab, researchers were already looking at whether prior infections could somehow prime the immune systems in people with Alzheimer’s disease pathology in the brain, making them more susceptible to worse outcomes over time as part of the Longitudinal Innate Immunity and Aging (LIIA).
“Even before the pandemic hit, there had been evidence to suggest that people with Alzheimer’s disease, if they developed a significant respiratory infection or other infection, tended to show worsening of their memory problems compared to people with Alzheimer’s who didn’t have an infection,” Bettcher said.
“Then the pandemic hit with one of the most transmissible viruses that we’ve ever seen,” she said, prompting her proposal for the NIH grant to specifically study SARS-CoV-2 exposure’s potential effects on Alzheimer’s symptoms. Recruitment is underway.
Having an uncontrolled pandemic that directly relates to the immune system and threatens many vulnerable populations is concerning and does call for heightened research, Bettcher said.
“I’ve been very impressed and heartened to see how many studies that have been started at our university to try to advance our understanding of COVID. It is urgent that we implement more studies to get to the bottom of this.”