Medical College of Wisconsin Research Team Unravels Gut Microbiome’s Connection to Alzheimer’s Disease

Drs. Malgorzata Franczak (left) and Laura Umfleet recently conducted a study that examines the gut-brain axis and its impact on cognitive dysfunction.

Several years ago, neuropsychologist Laura Umfleet, PsyD, ABPP-CN, evaluated a patient following an infection in the mouth that had spread to their brain. As a then assistant, now associate professor of neurology at the Medical College of Wisconsin (MCW), Dr. Umfleet was intrigued. What causal pathways were involved that led from an oral infection to brain damage and cognitive dysfunction?

She began digging into the research. With her interests in neurodegenerative conditions such as Alzheimer’s disease, she expanded her search to reading up on how chronic inflammation and infection may trigger the development of the disease.

Nearby on campus, Malgorzata Franczak, MD, GME ’98, FEL ’99, professor of neurology, had questions of her own. An expert in neurodegenerative disorders, Dr. Franczak knew that Alzheimer’s patients had elevated levels of certain proteins in their brains. But so far, researchers had not come up with a way to turn this information into effective medical treatments. Could that be, in part, because this wasn’t the only answer to unlocking the mystery of Alzheimer’s?

When Dr. Franczak was looking for a partner in 2018 to grow research in MCW’s Memory Disorders Program, she turned to Dr. Umfleet, who had come to MCW as a postdoctoral fellow in 2012.

“We had worked together clinically, and we knew that it would be a fantastic partnership for research, too,” Dr. Umfleet says. “We wanted to put MCW on the map for neurodegenerative research.”

Through novel imaging techniques and participant studies, the team – which includes partners in radiology and microbiology – has begun to unravel the gut-brain mechanisms behind neurodegenerative diseases like Alzheimer’s.

The story, it turns out, is not as simple as proteins in the brain. In fact, the story may start with the bacteria in the gut and mouth and their bidirectional communication pathways with the brain.

Cognitive Impairment and Its Relationship to the Microbiome

Alzheimer’s disease affects more than 7 million people in the United States – a number that’s expected to rise to nearly 13 million by 2050. Health and long-term care costs for people living with dementia were projected to reach $384 billion last year.

While pharmaceutical companies have released medications that remove proteins from Alzheimer’s patients’ brains, studies have shown that they do little to stop the progression of the disease.

Recently, researchers have looked at another Alzheimer’s culprit: bacteria in the gut.

The nearly 100 trillion bacteria and viruses in our digestive systems not only help digest food, they also play a role in immunity and overall health. This ecosystem includes both good and bad bacteria, viruses, and other microbial organisms. Over the past decade, researchers have observed higher levels of bad bacteria in conditions such as obesity, cancer, and cardiovascular disease.

Because these bacteria can access the brain through a gut-brain axis, they have also been implicated in neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

Franczak and Umfleet set their sights on helping to figure out why. They partnered with John Kirby, PhD, professor and chair of microbiology and immunology, and Yang Wang, MD, PhD, a professor of radiology who has developed novel MRI techniques.

They then recruited study volunteers – 30 healthy patients and 30 who were diagnosed with mild cognitive impairment due to Alzheimer’s disease – and had them undergo neuropsychological testing, a blood draw, an MRI scan, and stool collection.

Their stool collections underwent metagenomic sequencing to identify bacterial strains and viruses of bacteria correlated with neurovascular functioning and cognition.

With their preliminary data of 10 controls and 14 participants with mild cognitive impairment, the research team found that certain pro-inflammatory gut bacteria and viruses were more abundant in the group with mild cognitive impairment and were associated with neurovascular and cognitive dysfunction.

“Likewise, the good bacteria were associated with better neurovascular functioning and better cognition,” Dr. Umfleet says. The results were published in the journal Brain Science.

Bacteria Could Become Biomarkers of Disease

While much work remains to be done, the team’s findings offer a promising new direction for the diagnosis of Alzheimer’s disease. In the future, physicians may be able to use bacterial and viral signatures in the gut as early biomarkers of the disease, offering a simple, noninvasive way to identify those at risk before significant clinical symptoms emerge or worsen. This line of research could also open the door to new therapeutic strategies aimed at disease prevention.

“We are desperate not only for much better treatment of patients but also better identification of patients,” Dr. Franczak says. “With this research, as new treatments are developed, we could find patients at an early stage and monitor these bacterial biomarkers.”

Alzheimer’s disease is a complex biological condition influenced by many factors including genetics, aging, inflammation, and metabolic and vascular health. Still, uncovering how gut microbial communities interact with the brain offer powerful new insights and a hope for a better future to treat this debilitating disease, the researchers say.

Their gut-brain axis research recently expanded to examining normal aging and preclinical (asymptomatic) Alzheimer’s disease. They plan to conduct a longitudinal study to study how other microbial systems, like bacteria and viruses in the mouth, could be implicated in early Alzheimer’s disease. Their research is supported by the Daniel M. Soref Charitable Trust and Elizabeth T. and James B. Wigdale Innovation Fund for Memory Disorders, with additional resources from MCW.

The key to their successful partnership is open communication across disciplines.

“MCW is a great place for breaking down research silos and collaborating on projects that could have major impact,” Dr. Umfleet says.